||Hiroyuki Honda, Motoi Yoshimura, Hajime Arahata, Kaoru Yagita, Shoko Sadashima, Hideomi Hamasaki, Masahiro Shijo, Sachiko Koyama, Hideko Noguchi, Naokazu Sasagasako, Mutated FUS in familial amyotrophic lateral sclerosis involves multiple hnRNPs in the formation of neuronal cytoplasmic inclusions, Journal of Neuropathology & Experimental Neurology, 10.1093/jnen/nlac124, 2022.12.
||Hideko Noguchi, Sachiko Koyama, Kaoru Yagita, Masahiro Shijo, Kosuke Matsuzono, Hideomi Hamasaki, Takaaki Kanemaru, Tsuyoshi Okamoto, Keita Kai, Shinichi Aishima, Koji Abe, Naokazu Sasagasako, Hiroyuki Honda, Silence of resident microglia in GPI anchorless prion disease and activation of microglia in Gerstmann— Sträussler—Scheinker disease and sporadic Creutzfeldt—Jakob disease, Journal of Neuropathology and Experimental Neurology, 10.1093/jnen/nlac098, 2022.11.
||Sachiko Koyama, Hideko Noguchi, Kaoru Yagita, Hideomi Hamasaki, Masahiro Shijo, Motoi Yoshimura, Kohei Inoshita, Naokazu Sasagasako, Hiroyuki Honda
, Characteristic distribution and molecular properties of normal cellular prion protein in human endocrine and exocrine tissues , Scientific Reports, 2022.10.
||Kaoru Yagita, Hideko Noguchi, Sachiko Koyama, Hideomi Hamasaki, Takashi Komori, Shinichi Aishima, Takayuki Kosaka, Mitsuharu Ueda, Yoshihiro Komohara, Akihiro Watanabe, Naokazu Sasagasako, Toshiharu Ninomiya, Yoshinao Oda, Hiroyuki Honda, Chronological Changes in the Expression Pattern of Hippocampal Prion Proteins During Disease Progression in Sporadic Creutzfeldt-Jakob Disease MM1 Subtype, Journal of Neuropathology and Experimental Neurology, 2022.10.
||Kaoru Yagita, Naokazu Sasagasako, Sachiko Koyama, Hideko Noguchi, Hiroyuki Honda
, Amyotrophic lateral sclerosis with TDP-43 abnormalities exhibiting globular glial tau inclusions in frontotemporal lobes and pallido-nigral system , Neuropathology, 2022.08.
||Min Chu 1 , Kexin Xie 1 , Jing Zhang 1 , Zhongyun Chen 1 , Imad Ghorayeb 2 3 4 , Sven Rupprecht 5 , Anthony T Reder 6 , Arturo Garay 7 , Hiroyuki Honda 8 , Masao Nagayama 9 , Qi Shi 10 , Shuqin Zhan 1 , Haitian Nan 1 11 , Jiatang Zhang 12 , Hongzhi Guan 13 , Li Cui 14 , Yanjun Guo 15 , Pedro Rosa-Neto 16 , Serge Gauthier 16 , Jiawei Wang 15 , Xiaoping Dong 17 , Liyong Wu 18 19
Proposal of new diagnostic criteria for fatal familial insomnia , Journal of Neurology
||Yagita K, Honda H, Ohara T, Hamasaki H, Koyama S, Noguchi H, Mihara A, Nakazawa T, Hata J, Ninomiya T, Iwaki T., A Comparative Study of Site-Specific Distribution of Aging-Related Tau Astrogliopathy and Its Risk Factors Between Alzheimer Disease and Cognitive Healthy Brains: The Hisayama Study., J Neuropathol Exp Neurol, 2022.01.
||Kosuke Matsuzono, Younhee Kim, Hiroyuki Honda, Yuhei Anan, Yuto Hashimoto, Ichiya Sano, Toru Iwaki , Tetsuyuki Kitamoto, Shigeru Fujimoto, Optic nerve atrophy and visual disturbance following PRNP Y162X truncation mutation, J Neurol Sci., 2021.08.
||Hideomi Hamasaki 1 , Masahiro Shijo 1 2 , Ayaka Nakamura 1 , Hiroyuki Honda 1 , Yuichi Yamada 3 , Yoshinao Oda 3 , Tomoyuki Ohara 4 5 , Toshiharu Ninomiya 5 6 , Toru Iwaki 1
, Concurrent cardiac transthyretin and brain β amyloid accumulation among the older adults: The Hisayama study , Brain Pathology, 2022.01.
||Matsuzono K, Kim Y, Honda H, Anan Y, Tsunoda M, Amano Y, Fukusima N, Iwaki T, Kitamoto T, Fujimoto S., Prion gene PRNP Y162X truncation mutation can induce a refractory esophageal achalasia. , Am J Gastoenterol, 2021.06.
||Hiroyuki H, Kosuke M, Kota S, Masayoshi F, Satoshi S, Chiaki F, Tetsuyuki K, Shigeru F, Koji A, Toru I, Detection of cutaneous prion protein deposits could help diagnose GPI-anchorless prion disease with neuropathy, European Journal of Neurology, 2021.01, Background and purpose: To investigate prion protein (PrP) deposits in cutaneous tis- sues of patients of glycosylphosphatidylinositol (GPI)-anchorless prion diseases with neuropathy.
Methods: Cutaneous tissue samples from three patients with GPI-anchorless prion diseases were obtained, two cutaneous biopsy samples from the lower leg of Case 1 (Y162X) and Case 3 (D178fs25), and a cutaneous sample taken from the abdomen during an autopsy of Case 2 (D178fs25). We performed immunohistochemistry for PrP to look for abnormal PrP deposits.
Results: PrP deposits were observed in the dermal papilla, the sweat glands, the hair follicles, the arrector pili muscles, and peripheral nerves of all examined cases of GPI- anchorless prion disease with neuropathy. The abnormal PrP accumulation was fre- quently localized at the basement membrane, and colocalized with laminin.
Conclusion: Immunohistochemical detection of PrP in cutaneous samples could be used to definitively diagnose GPI-anchorless PrP disease with neuropathy..
||Hiroyuki Honda, Shinichirou Mori, Akihito Watanabe, Nokazu Sasagasako, Shoko Sadashima, Dong Trang, Katsuya Satoh, Noriyuki Nishida, Toru Iwaki, Abnormal prion protein depositions with high seeding activities in the skeletal muscle, femoral nerve, and scalp of the autopsied case of sporadic Creutzfeldt–Jakob disease, Neuropathology, 2020.12, We report the general autopsy findings of abnormal prion protein (PrP) deposits with their seeding activities, as assessed by the real-time quaking-induced conversion (RT-QuIC) method, in a 72-year-old female patient with sporadic Creutzfeldt–Jakob disease (sCJD). At 68 years of age, she presented with gait disturbance and visual dis- orders. Electroencephalography showed periodic synchro- nous discharge. Myoclonus was also observed. A genetic test revealed that PRNP codon 129 was methionine/methi- onine (MM). She died of pneumonia three years and four months after disease onset, and a general autopsy was performed. The brain weighed 650 g and appeared markedly atrophic. Immunohistochemistry for PrP rev- ealed synaptic PrP deposits and coarse PrP deposits in the cerebral cortices, basal ganglia, cerebellum, and brainstem. Western blot analysis identified type 1 proteinase-K- resistant PrP in frontal cortex samples. PrP deposits were also observed in systemic organs, including the femoral nerve, psoas major muscle, abdominal skin, adrenal medulla, zona reticularis of the adrenal gland, islet cells of the pancreas, and thyroid gland. The RT-QuIC method revealed positive seeding activities in all examined organs, including the frontal cortex, femoral nerve, psoas major muscle, scalp, abdominal skin, adrenal gland, pancreas, and thyroid gland. The following 50% seeding dose (SD50) values were 9.5 (frontal cortex); 8 0.53 (femoral nerve); 7 0.53 (psoas major muscle); and 7.88 0.17 (scalp). The SD50 values for the adrenal gland, dermis, pancreas, and thyroid gland were 6.12 0.53, 5.25, 4.75, and 4.5, respectively. PrP deposits in general organs may be associated with long-term disease duration. This case indicated the necessity for general autopsies in sCJD cases to establish strict infection control procedures for surgical treatment and to examine certain organs..
||Motoi Yoshimura, Hiroyuki Honda, Naokazu Sasagasako, Shinichiro Mori, Hideomi Hamasaki, Satoshi O Suzuki, Takashi Ishii, Toshiharu Ninomiya, Jun-Ichi Kira, Toru Iwaki
, PCBP2 Is Downregulated in Degenerating Neurons and Rarely Observed in TDP-43-Positive Inclusions in Sporadic Amyotrophic Lateral Sclerosis, J Neuropathol Exp Neurol
||Schinichiro Mori, Hiroyuki Honda, Hideomi Hamasaki, Naokazu Sasagasako, Satoshi O Suzuki, Hirokazu Furuya, Takayuki Taniwaki, Toru Iwaki, TDP-43 proteinopathy and lysosomal abnormalities in spastic paraplegia 11, Neuropathology, 2020.12.
||Kosuke Matsuzono, Younhee Kim, Hiroyuki Honda, Yuhei Anan, Masato Tsunoda, Yusuke Amano, Noriyoshi Fukusima, Toru Iwaki, Tetsuyuki Kitamoto, Shigeru Fujimoto, Prion Gene PRNP Y162X Truncation Mutation Can Induce a Refractory Esophageal Achalasia, American Journal of Gastroenterology , 2020.11.
||Sadashima S, Honda H, Suzuki SO, Shijo M, Aishima S, Kai K, Kira J, Iwaki T, Accumulation of Astrocytic Aquaporin 4 and Aquaporin 1 in Prion Protein Plaques., Journal of neuropathology and experimental neurology , 2020.04.
||Shinichirou Mori, Hiroyuki Honda, Hideomi Hamasaki, Sakae Nobutaka, Naokazu Sasagasako, Hirokazu Furuya, Toru Iwaki, , Symmetrical glial hyperplasia in the brainstem of fibrodysplasia ossificans progressiva, Neuropathology, 2020.12.
||Hideomi Hamasaki, Hiroyuki Honda, Satoshi O. Suzuki, Masahiro Shijo, Tomoyuki Ohara, Yozo Hatabe, Tsuyoshi Okamoto, Toshiharu Ninomiya, Toru Iwaki, Tauopathy in basal ganglia involvement is exacerbated in a subset of patients with Alzheimer's disease
The Hisayama study, Alzheimer's and Dementia: Diagnosis, Assessment and Disease Monitoring, 10.1016/j.dadm.2019.04.008, 11, 415-423, 2019.12, Introduction: We have conducted the pathological cohort study of autopsied cases of Hisayama residents to reveal a recent trend of dementia-related pathology. We noticed a trend of putaminal involvement of Alzheimer's disease (AD) with parkinsonism. Then, we investigated the accurate prevalence of neurological diseases with putaminal AD pathology in the general population. Methods: We examined a series of 291 autopsies in the Hisayama study and performed image analysis of immunohistochemistry for microtubule-associated protein tau (MAPT) and amyloid β. Results: Approximately 65.6% and 36.1% of cases showed putaminal MAPT and amyloid deposits, respectively. Diffuse deposits of them were mainly found in the AD cases. Putaminal MAPT was highly associated with AD-related pathological criteria. Four of 22 cases with severe putaminal MAPT deposition were documented as having developed parkinsonism. Discussion: Severe MAPT accumulation in the basal ganglia was closely related to the development of AD pathology and could occur most frequently in AD cases without comorbidities..
||Shinichiro Mori, Hiroyuki Honda, Takashi Ishii, Motoi Yoshimura, Naokazu Sasagasako, Satoshi O. Suzuki, Takayuki Taniwaki, Toru Iwaki, Expanded polyglutamine impairs normal nuclear distribution of fused in sarcoma and poly (rC)-binding protein 1 in Huntington's disease, Neuropathology, 10.1111/neup.12600, 39, 5, 358-367, 2019.10, Huntington's disease (HD) is an inherited neurodegenerative disease caused by a polyglutamine repeat expansion in the huntingtin protein. Immunohistochemical studies using the 1C2 antibody for polyglutamine expansion have detected characteristic intranuclear inclusions (INIs) in affected neurons in HD. Further, in vitro and mouse models of HD have shown that the INIs recruit several proteins relating to RNA splicing and translation. In the present study, we immunohistochemically investigated the association of INIs with various heterogeneous nuclear ribonucleoproteins in the cerebral cortex of four autopsy cases of HD. Fused in sarcoma (FUS) was colocalized with 1C2-positive nuclear inclusions in all examined cases. Localization of poly (rC)-binding protein 1 (PCBP1) in 1C2-positive nuclear inclusions was also observed. Double immunofluorescence revealed complete or partial loss of the normal, diffuse nuclear distribution of FUS or PCBP1 in neurons with 1C2-positive nuclear inclusions. This maldistribution of FUS in cortical neurons suggests a severe disturbance of messenger RNA processing, which may be a common pathogenetic mechanism of FUS-related familial amyotrophic lateral sclerosis..
||Hiroyuki Honda, Masaki Matsumoto, Masahiro Shijo, Hideomi Hamasaki, Shoko Sadashima, Satoshi O. Suzuki, Shinichi Aishima, Keita Kai, Keiichi I. Nakayama, Naokazu Sasagasako, Toru Iwaki, Frequent Detection of Pituitary-Derived PrPres in Human Prion Diseases, Journal of neuropathology and experimental neurology, 10.1093/jnen/nlz075, 78, 10, 922-929, 2019.10, Human prion diseases including sporadic Creutzfeldt-Jakob disease (sCJD), inherited prion diseases, and acquired human prion diseases are lethal neurodegenerative diseases. One of the major sources of iatrogenic Creutzfeldt-Jakob disease was human growth hormone (hGH-iCJD) derived from contaminated cadaveric pituitaries. The incidence of hGH-iCJD has decreased since changing from growth hormone extracted from human cadaveric pituitaries to recombinant pituitary hormones. However, extensive analysis on the localization and detecting of abnormal prion protein in the pituitary gland are limited. In this study, we examined 9 autopsied brains and pituitary glands from 6 patients with prion disease (3 Gerstmann-Sträussler-Scheinker disease, 2 sCJD, and 1 dura mater graft-associated CJD) and 3 individuals with nonprion diseases. Western blot analysis of pituitary samples demonstrated unique glycoforms of normal cellular prion protein with molecular weights of 30-40 kDa, which was higher than the typical 25-35 kDa prion protein in brains. Proteomic analysis also revealed prion protein approximately the molecular weight of 40 kDa in pituitary samples. Moreover, proteinase K-resistant Prion protein was frequently detected in pituitary samples of the prion diseases. Immunohistochemistry for Prion protein revealed mosaic cellular distribution preferentially in growth hormone- or prolactin-producing cells..
||Masahiro Shijo, Hideomi Hamasaki, Hiroyuki Honda, Satoshi O. Suzuki, Masaki Tachibana, Tetsuro Ago, Takanari Kitazono, Koji Iihara, Toru Iwaki, Upregulation of Annexin A1 in Reactive Astrocytes and Its Subtle Induction in Microglia at the Boundaries of Human Brain Infarcts, Journal of neuropathology and experimental neurology, 10.1093/jnen/nlz079, 78, 10, 961-970, 2019.10, Annexin A1 (ANXA1) has multiple functions, including anti-inflammatory effects, and is thought to be neuroprotective in various pathophysiologies of the central nervous system. The importance of ANXA1 in microglia and endothelial cells in ischemic environments in the brain has been recognized, but its detailed behavior in astrocytes in the ischemic brain remains unknown. Using immunohistochemistry, we therefore assessed the altered distribution of ANXA1 in human brain infarcts using 14 autopsied samples and 18 surgical samples. Elevated expression of ANXA1 was observed in reactive astrocytes in peri-infarct regions. ANXA1 accumulated at the cell periphery and in swollen cytoplasmic processes of reactive astrocytes, as well as at the rim of vacuoles at the boundary of necrosis, and colocalized with aberrantly distributed aquaporin 4 and excitatory amino acid transporter 1. Foamy macrophages in the necrotic core also expressed abundant ANXA1, whereas resident microglia at the boundary of necrosis rarely showed intrinsic expression of ANXA1. This characteristic distribution of ANXA1 in human brain infarcts may represent the good adaptability of reactive astrocytes to ischemic damage..
||Fujii T, Takase KI, Honda H, Kawamura N, Yamasaki R, Urata M, Uchiumi T, Iwaki T, Kira JI, A case of toxic myopathy with multiple deletions in mitochondrial DNA associated with long-term use of oral anti-viral drugs for hepatitis B, Neuropathology, 2019.04.
||Takayuki Fujii, Kei ichiro Takase, Hiroyuki Honda, Nobutoshi Kawamura, Ryo Yamasaki, Michiyo Urata, Takeshi Uchiumi, Toru Iwaki, Jun ichi Kira, Toxic myopathy with multiple deletions in mitochondrial DNA associated with long-term use of oral anti-viral drugs for hepatitis B
A case study, Neuropathology, 10.1111/neup.12548, 39, 2, 162-167, 2019.04, Oral nucleoside analogs (NAs) reduce hepatitis B virus (HBV) replication by inhibiting HBV DNA polymerase. However, NAs can also affect human mitochondrial DNA (mtDNA) polymerase, which can lead to mtDNA depletion (quantitative abnormality). Indeed, several mitochondrial myopathy cases have been reported in which a reduced mtDNA copy number was induced by oral NAs for hepatitis B. Herein, we report a case of toxic myopathy with multiple mtDNA deletions (qualitative abnormality) associated with long-term use of NAs for hepatitis B. A 68-year-old woman, who underwent long-term treatment with lamivudine and adefovir for chronic hepatitis B, developed proximal muscle weakness in the four extremities. Neurological examination showed mild proximal muscle weakness and atrophy in the four extremities. Upon admission to our hospital, her blood lactate/pyruvate ratio during an aerobic exercise test was elevated. Myogenic patterns were observed in lower limb muscles on electromyographic examination. Muscle magnetic resonance imaging revealed diffuse atrophy of proximal muscles in the four extremities with no signal changes. A biopsy from the biceps brachii muscle showed an abnormally large variation in fiber size, scattered muscle fibers with decreased cytochrome c oxidase activity, and ragged-red fibers. Analysis of mtDNA from skeletal muscle revealed no decrease in copy number but increased incidence of multiple deletions, including a deletion of 4977 base pairs (known as the common deletion) reflecting oxidative stress-induced mtDNA damage. This case study indicates that long-term oral antiviral therapy for hepatitis B can induce chronic oxidative damage to mtDNA resulting in qualitative mtDNA abnormalities and toxic myopathy..
||Takayuki Fujii, Hiroyuki Honda, Ryo Yamasaki, Toru Iwaki, Jun Ichi Kira, Multiple mtDNA deletions due to mitochondrion toxicity of anti-hepadnaviral drugs
Comments to the letter from J. Finsterer, Neuropathology, 10.1111/neup.12563, 39, 4, 326-327, 2019.01.
||Chang Shen, Hiroyuki Honda, Satoshi Suzuki, Norihisa Maeda, Masahiro Shijo, Hideomi Hamasaki, Naokazu Sasagasako, Naoki Fujii, Toru Iwaki, Dynactin is involved in Lewy body pathology, Neuropathology, 10.1111/neup.12512, 38, 6, 583-590, 2018.12, Dynactin forms a protein complex with dynein that retrogradely transports cargo along microtubules. Dysfunction of this dynein-dynactin complex causes several neurodegenerative diseases such as Perry syndrome, motor neuron diseases and progressive supranuclear palsy. Recently, we reported colocalization of phosphorylated α-synuclein (p-SNCA) and the largest subunit of dynactin (DCTN1) in Lewy body (LB)-like structures in Perry syndrome. Previous reports have not focused on the relationship between dynactin and synucleinopathies. Thus, we examined autopsied human brains from patients with Parkinson's disease, dementia with LBs, and multiple system atrophy using immunohistochemistry for p-SNCA, DCTN1, dynactin 2 (DCTN2, dynamitin) and dynein cytoplasmic 1 intermediate chain 1 (DYNC1I1). We also examined microtubule affinity-regulating kinases (MARKs), which phosphorylate microtubule-associated proteins and trigger microtubule disruption. Both brainstem-type and cortical LBs were immunopositive for DCTN1, DCTN2, DYNC1I1 and p-MARK and their staining often overlapped with p-SNCA. Lewy neurites were also immunopositive for DCTN1, DCTN2 and DYNC1I1. However, p-SNCA-positive inclusions of multiple system atrophy, which included both glial and neuronal cytoplasmic inclusions, were immunonegative for DCTN1, DCTN2, DYNC1I1 and p-MARK. Thus, immunohistochemistry for dynein-dynactin complex molecules, especially DCTN1, can clearly distinguish LBs from neuronal cytoplasmic inclusions. Our results suggest that dynactin is closely associated with LB pathology..
||Norihisa Maeda, Hiroyuki Honda, Satoshi Suzuki, Naoki Fujii, Jun-Ichi Kira, Toru Iwaki, Mitochondrial dysfunction and altered ribostasis in hippocampal neurons with cytoplasmic inclusions of multiple system atrophy, Neuropathology, 10.1111/neup.12482, 38, 4, 361-371, 2018.08, Multiple system atrophy (MSA) is a sporadic adult-onset neurodegenerative disease. It has recently been shown that patients with MSA accompanied by cognitive decline display numerous neuronal cytoplasmic inclusions (NCIs) in the limbic neurons. We examined potential mechanisms underlying the formation of these NCIs by determining of mitochondrial function and statuses of RNA processing by analyzing 12 pathologically confirmed cases of MSA. Among them, four had cognitive impairment Semiquantitative evaluation using immunohistochemistry analyses revealed a significantly greater NCI burden in the hippocampal cornu ammonis 1 (CA1) subfield, subiculum, and amygdala in the cases with cognitive impairments compared with those without cognitive impairment. Immunofluorescent staining revealed that limbic neurons with NCIs often accelerated production of reactive oxygen species (ROS) and degraded mitochondrial quality control. Immunofluorescent staining also revealed that neurons with these NCIs translocated heterogeneous nuclear ribonucleoprotein A1 (HNRNPA1) from the nucleus and aggregated abnormally at the perinuclear rim. Since the NCIs in the hippocampal neurons of MSA with cognitive impairments were more numerous, the neuronal mitochondrial dysfunction and altered ribostasis observed in NCI formation may be involved in the hippocampal degeneration of MSA..
||Hiroyuki Honda, Naokazu Sasagasako, Chang Shen, Masahiro Shijo, Hideomi Hamasaki, Satoshi Suzuki, Yoshio Tsuboi, Naoki Fujii, Toru Iwaki, DCTN1 F52L mutation case of Perry syndrome with progressive supranuclear palsy-like tauopathy, Parkinsonism and Related Disorders, 10.1016/j.parkreldis.2018.02.038, 51, 105-110, 2018.06, Introduction: Perry syndrome is a rapidly progressive, autosomal dominant parkinsonism characterized by central hypoventilation, depression and severe weight loss. To date, eight DCTN1 mutations have been identified associated with Perry syndrome. A novel F52L DCTN1 mutation case of Perry syndrome is characterized by late-onset parkinsonism and frontotemporal atrophy. Methods: A Japanese woman suffered from slowly progressing parkinsonism since age 48. At age 59, she developed central hypoventilation, and required breathing assistance. Gene analysis identified a p.F52L mutation in DCTN1 and she was diagnosed with Perry syndrome. She died of aspiration pneumonia at age 74. Results: Postmortem examination revealed severe neuronal loss in the substantia nigra and the putamen. Immunohistochemistry for DCTN1 revealed many abnormal aggregates, mainly in neurons in the brainstem and basal ganglia. Additionally, numerous abnormal phosphorylated tau deposits including neurofibrillary tangles, tuft-shaped astrocytes and coiled bodies were observed mainly in the basal ganglia, brainstem and cerebellum. These correspond with the neuropathologic criteria for progressive supranuclear palsy. Colocalization of DCTN1 and tau were occasionally seen. Colocalization of phosphorylated α-synuclein and DCTN1 were also observed in Lewy body-like structures in oculomotor nuclei. Phosphorylated TARDBP-positive neuronal cytoplasmic inclusions were few. Conclusion: In conjunction with long disease duration and aging, our findings suggest that the F52L DCTN1 mutation may evoke severe tauopathy and moderate α-synucleinopathy..
||Reiji Hommyo, Satoshi Suzuki, Nona Abolhassani, Hideomi Hamasaki, Masahiro Shijo, Norihisa Maeda, Hiroyuki Honda, Yusaku Nakabeppu, Toru Iwaki, Expression of CRYM in different rat organs during development and its decreased expression in degenerating pyramidal tracts in amyotrophic lateral sclerosis, Neuropathology, 10.1111/neup.12466, 38, 3, 247-259, 2018.06, The protein μ-crystallin (CRYM) is a novel component of the marsupial lens that has two functions: it is a key regulator of thyroid hormone transportation and a reductase of sulfur-containing cyclic ketimines. In this study, we examined changes of the expression pattern of CRYM in different rat organs during development using immunohistochemistry and immunoblotting. As CRYM is reportedly expressed in the corticospinal tract, we also investigated CRYM expression in human cases of amyotrophic lateral sclerosis (ALS) using immunohistochemistry. In the rat brain, CRYM was expressed in the cerebral cortex, basal ganglia, hippocampus and corticospinal tract in the early postnatal period. As postnatal development progressed, CRYM expression was restricted to large pyramidal neurons in layers V and VI of the cerebral cortex and pyramidal cells in the deep layer of CA1 in the hippocampus. Even within the same regions, CRYM-positive and negative neurons were distributed in a mosaic pattern. In the kidney, CRYM was expressed in epithelial cells of the proximal tubule and mesenchymal cells of the medulla in the early postnatal period; however, CRYM expression in the medulla was lost as mesenchymal cell numbers decreased with the rapid growth of the medulla. In human ALS brains, we observed marked loss of CRYM in the corticospinal tract, especially distally. Our results suggest that CRYM may play roles in development of cortical and hippocampal pyramidal cells in the early postnatal period, and in the later period, performs cell-specific functions in selected neuronal populations. In the kidney, CRYM may play roles in maturation of renal function. The expression patterns of CRYM may reflect significance of its interactions with T3 or ketimines in these cells and organs. The results also indicate that CRYM may be used as a marker of axonal degeneration in the corticospinal tract..
||Yuri Mizuno, Norihisa Maeda, Hideomi Hamasaki, Hajime Arahata, Naokazu Sasagasako, Hiroyuki Honda, Naoki Fujii, Toru Iwaki, Four-repeat tau dominant pathology in a congenital myotonic dystrophy type 1 patient with mental retardation, Brain Pathology, 10.1111/bpa.12603, 28, 3, 431-433, 2018.05.
||Masahiro Shijo, Hiroyuki Honda, Satoshi Suzuki, Hideomi Hamasaki, Masaaki Hokama, Nona Abolhassani, Yusaku Nakabeppu, Toshiharu Ninomiya, Takanari Kitazono, Toru Iwaki, Association of adipocyte enhancer-binding protein 1 with Alzheimer's disease pathology in human hippocampi, Brain Pathology, 10.1111/bpa.12475, 28, 1, 58-71, 2018.01, Adipocyte enhancer binding protein 1 (AEBP1) activates inflammatory responses via the NF-κB pathway in macrophages and regulates adipogenesis in preadipocytes. Up-regulation of AEBP1 in the hippocampi of patients with Alzheimer's disease (AD) has been revealed by microarray analyses of autopsied brains from the Japanese general population (the Hisayama study). In this study, we compared the expression patterns of AEBP1 in normal and AD brains, including in the hippocampus, using immunohistochemistry. The subjects were 24 AD cases and 52 non-AD cases. Brain specimens were immunostained with antibodies against AEBP1, tau protein, amyloid β protein, NF-κB, GFAP and Iba-1. In normal brains, AEBP1 immunoreactivity mainly localized to the perikarya of hippocampal pyramidal neurons, and its expression was elevated in the pyramidal neurons and some astrocytes in AD hippocampi. Although AEBP1 immunoreactivity was almost absent in neurons containing neurofibrillary tangles, AEBP1 was highly expressed in neurons with pretangles and in the tau-immunopositive, dystrophic neurites of senile plaques. Nuclear localization of NF-κB was also observed in certain AEBP1-positive neurons in AD cases. Comparison of AD and non-AD cases suggested a positive correlation between the expression level of AEBP1 and the degree of amyloid β pathology. These findings imply that AEBP1 protein has a role in the progression of AD pathology..
||Masahiro Shijo, Hiroyuki Honda, Sachiko Koyama, Koji Ishitsuka, Koichiro Maeda, Junya Kuroda, Mitsugu Tanii, Takanari Kitazono, Toru Iwaki, Dura mater graft-associated Creutzfeldt-Jakob disease with 30-year incubation period, Neuropathology, 10.1111/neup.12359, 37, 3, 275-281, 2017.06, Over 60% of all patients with dura mater graft-associated Creutzfeldt-Jakob disease (dCJD) have been diagnosed in Japan. The incubation period has ranged from 1 to 30 years and the age at onset from 15 to 80 years. Here, we report a 77-year-old male Japanese autopsied dCJD case with the longest incubation period so far in Japan. He received a cadaveric dural graft at the right cranial convexity following a craniotomy for meningioma at the age of 46. At 30 years post-dural graft placement, disorientation was observed as an initial symptom of dCJD. He rapidly began to present with inconsistent speech, cognitive impairment and tremor of the left upper extremity. Occasional myoclonic jerks were predominantly observed on the left side. Brain MRI presented hyperintense signals on diffusion-weighted and T2-weighted images, at the right cerebral cortex. The most hyperintense lesion was located at the right parietal lobe, where the dura mater graft had been transplanted. Single-photon emission CT scan showed markedly decreased cerebral blood flow at the right parietal lobe. EEG revealed diffuse and slow activities with periodic sharp-wave complex discharges seen in the right parietal, temporal and occipital lobes. He died of pneumonia 9 months after onset. Brain pathology revealed non-plaque-type dCJD. Laterality of neuropathological changes, including spongiform change, neuronal loss, gliosis or PrP deposits, was not evident. Western blot analysis showed type 1 PrPCJD. Alzheimer-type pathology and PSP-like pathology were also observed..
||Yu Tzu Wu, Alexa S. Beiser, Monique M.B. Breteler, Laura Fratiglioni, Catherine Helmer, Hugh C. Hendrie, Hiroyuki Honda, M. Arfan Ikram, Kenneth M. Langa, Antonio Lobo, Fiona E. Matthews, Tomoyuki Ohara, Karine Pérès, Chengxuan Qiu, Sudha Seshadri, Britt Marie Sjölund, Ingmar Skoog, Carol Brayne, The changing prevalence and incidence of dementia over time-current evidence, Nature Reviews Neurology, 10.1038/nrneurol.2017.63, 13, 6, 327-339, 2017.06, Dementia is an increasing focus for policymakers, civil organizations and multidisciplinary researchers. The most recent descriptive epidemiological research into dementia is enabling investigation into how the prevalence and incidence are changing over time. To establish clear trends, such comparisons need to be founded on population-based studies that use similar diagnostic and research methods consistently over time. This narrative Review synthesizes the findings from 14 studies that investigated trends in dementia prevalence (nine studies) and incidence (five studies) from Sweden, Spain, the UK, the Netherlands, France, the USA, Japan and Nigeria. Besides the Japanese study, these studies indicate stable or declining prevalence and incidence of dementia, and some provide evidence of sex-specific changes. No single risk or protective factor has been identified that fully explains the observed trends, but major societal changes and improvements in living conditions, education and healthcare might have favourably influenced physical, mental and cognitive health throughout an individual's life course, and could be responsible for a reduced risk of dementia in later life. Analytical epidemiological approaches combined with translational neuroscientific research could provide a unique opportunity to explore the neuropathology that underlies changing occurrence of dementia in the general population..
||Hiroyuki Honda, Kensuke Sasaki, Hiroshi Takashima, Daisuke Mori, Sachiko Koyama, Satoshi Suzuki, Toru Iwaki, Different complicated brain pathologies in monozygotic twins with Gerstmann-Sträussler-Scheinker disease, Journal of Neuropathology and Experimental Neurology, 10.1093/jnen/nlx068, 76, 10, 854-863, 2017.01, Gerstmann-Sträussler-Scheinker disease (GSS) is an autosomal, dominantly inherited prion disease. In this study, we present different complicated brain pathologies determined postmortem of monozygotic GSS twin sisters. Case 1 showed cerebellar ataxia at the age of 58 years, and died at 66 years. Case 2 became symptomatic at the age of 75 years, and died at 79 years. There was a 17-year difference in the age of onset between the twins. Postmortem examination revealed numerous prion protein (PrP) plaques in the brains of both cases. The spongiform change and brain atrophy in case 1 were more severe compared with those in case 2. Western-blot analysis identified proteinase-resistant PrP (PrPres) at the molecular weight of 21-30 kDa and 8 kDa in the twins. Gel filtration revealed that PrPres was mainly composed of PrP oligomer. PrPres signal patterns were similar between the twins. Additionally, case 1 showed α-synucleinopathy and case 2 showed Alzheimer disease pathology. These different proteinopathies were involved in the amyloid plaque formations of both cases. The degree of GSS pathology was mainly related to disease duration. The amyloid plaque formations could be decorated by concomitant neuropathological changes such as a-synucleinopathy and tauopathy..
||Hideomi Hamasaki, Hiroyuki Honda, Tsuyoshi Okamoto, Sachiko Koyama, Satoshi Suzuki, Tomoyuki Ohara, Toshiharu Ninomiya, Yutaka Kiyohara, Toru Iwaki, Recent Increases in Hippocampal Tau Pathology in the Aging Japanese Population
The Hisayama Study, Journal of Alzheimer's Disease, 10.3233/JAD-160521, 55, 2, 613-624, 2017.01, Background: The Hisayama study is a prospective cohort study of lifestyle-related diseases that commenced in 1961. Through it, a significant increasing trend in the prevalence of Alzheimer's disease has been observed over the past 18 years. Objectives: We sought to investigate the increases in brain pathology related to Alzheimer's disease using automated MATLAB morphometric analyses for quantifying tau pathology. Methods: We examined a series of autopsied cases from Hisayama residents obtained between 1998 and 2003 (group A: 203 cases), and between 2009 and 2014 (group B: 232 cases). We developed custom software in MATLAB to analyze abnormal tau deposits quantitatively. Specimens were immunostained with both anti-amyloid-β-protein and anti-phosphorylated tau antibodies. Results: Both the Consortium to Establish a Registry for Alzheimer's Disease (CERAD) criteria for senile plaques and Braak stage for NFT were higher in group B. Morphometric analyses of the hippocampi also revealed a trend toward increased tau pathology in both men and women over 80 years of age in group B. The increases were also significant when the subjects were examined independently according to high or low CERAD scores and in all levels of AD neuropathologic change according to the National Institute on Aging-Alzheimer's Association guidelines (2012). Conclusion: We revealed a recent trend of increased tauopathy in the older people, which is partly independent of amyloid-β pathology..
||Hiroyuki Honda, Kensuke Sasaki, Hideomi Hamasaki, Masahiro Shijo, Sachiko Koyama, Tomoyuki Ohara, Toshiharu Ninomiya, Yutaka Kiyohara, Satoshi Suzuki, Toru Iwaki, Trends in autopsy-verified dementia prevalence over 29 years of the Hisayama study, Neuropathology, 10.1111/neup.12298, 36, 4, 383-387, 2016.08, We investigated the trends in dementia over the past 29 years in the town of Hisayama, Japan using 1266 autopsy specimens. The Hisayama study is a prospective cohort study of lifestyle-related diseases that was started in 1961. Clinical examination of dementia was started in 1985 with five detailed cross-sectional assessments conducted in 1985, 1992, 1998, 2005 and 2012. To examine the trends in dementia, we divided the 1266 autopsy samples into five groups according to the year of death: I (1986–1991, 257 cases), II (1992–1997, 268 cases), III (1998–2004, 318 cases), IV (2005–2011, 296 cases) and V (2012–2014, 127 cases). The prevalence of all-cause dementia significantly increased over time (28.4% in group I, 22.4% in group II, 32.1% in group III, 30.1% in group IV, 51.2% in group V; P for trend <0.001). A similar trend was observed for Alzheimer's disease (AD) (15.2%, 11.9%, 17.3%, 20.6% and 33.1%, respectively; P for trend <0.001). A significant increasing trend was observed in both men and women. A rapid increase in senile dementia of the NFT type (SD-NFT) in recent years was notable. Vascular dementia was the most common type of dementia in men prior to 2004; however, its prevalence decreased over time. Our study revealed that tauopathies, including AD and SD-NFT, significantly increased in the aged Japanese population over the course of this study. The neuritic plaque pathology of AD was associated with metabolic disorders such as insulin resistance and abnormal lipid metabolism, whereas the risk factors for tau pathology remain unclear. Although aging is considered one of the important risk factors accelerating tau pathology, there could be other risk factors associated with lifestyle diseases..
||K. Matsuzono, Hiroyuki Honda, K. Sato, R. Morihara, K. Deguchi, N. Hishikawa, T. Yamashita, S. Kono, Y. Ohta, Toru Iwaki, K. Abe, 'PrP systemic deposition disease'
Clinical and pathological characteristics of novel familial prion disease with 2-bp deletion in codon 178, European Journal of Neurology, 10.1111/ene.12905, 23, 1, 196-200, 2016.01, Background and purpose: A novel TYPE of prion disease associated mainly with autonomic-sensory polyneuropathy was reported by us previously. Methods: Here the autopsy pathology for patient 1 (the sister) and the clinical characteristics of her younger brother (patient 2) are newly reported. Polymerase chain reaction based restriction fragment length polymorphism analysis of the prion protein gene (PRNP) was performed on both patients and their father (normal control). Results: Polymerase chain reaction based restriction fragment length polymorphism analysis revealed a 2-bp deletion (CT) in codon 178 that causes an additional variable 25 amino acids at the C terminal, from the mutation site to the premature stop codon at codon 203, in both patients 1 and 2 but not in their father. The autopsy of patient 1 showed remarkable prion protein (PrP) deposits in the sympathetic ganglion and peripheral nerves, correlated to her severe autonomic sensory failure. PrP deposits were also found in the central nervous system and peripheral organs such as the heart, lung, stomach, jejunum, ileum, colon, urinary bladder and adrenal gland. The symptoms and biopsy findings of patient 2 were nearly the same as those reported previously for patient 1. His cognitive function was well preserved, but autonomic functions were severely impaired. His biopsied samples showed PrP deposits in the sural nerve and nerve plexuses of the stomach and colon. Conclusion: The present unique 2-bp deletion (CT) in codon 178 induced a 'PrP systemic deposition disease' such as pan-autonomic failure, sensory neuropathy and mild cognitive impairment with a specific pathology..
||Hiroyuki Honda, Kosuke Matsuzono, Soichiro Fushimi, Kota Sato, Satoshi Suzuki, Koji Abe, Toru Iwaki, C-terminal-deleted prion protein fragment is a major accumulated component of systemic PrP deposits in hereditary prion disease with a 2-Bp (CT) deletion in PRNP codon 178, Journal of Neuropathology and Experimental Neurology, 10.1093/jnen/nlw077, 75, 11, 1008-1019, 2016.01, Prion protein (PrP) has 2 glycosylated sites and a glycosylphosphatidylinositol (GPI) anchor on the C-terminal. Reports on genetic prion disease with GPI anchorless PrP are very limited. In this study, we characterized the molecular alterations of mutated PrP in a 37-year-old female autopsy case with a recently identified PRNP mutation involving a 2-bp deletion in codon 178 that results in a premature stop codon mutation in codon 203. Postmortem examination revealed numerous irregularly shaped coarse PrP deposits and multicentric plaques in the brain that were mainly comprised of C-terminal deleted abnormal PrP primarily derived from the mutant allele. Additionally, abnormal PrP deposits were detected in almost all other examined organs. PrP was mainly deposited in peripheral nerves, smooth muscles, and blood vessels in non-CNS tissues. Western blot analysis after proteinase K treatment showed protease-resistant PrP (PrPres) signals with a molecular weight of 9 kDa; weak PrPres smear signals of 9 to 80 kDa were also noted. Gel filtration revealed that PrPres oligomers were mainly composed of the PrP fragments. In conclusion, the mutated PrP lacking that GPI anchor was truncated shortly and deposited in almost every examined organ..
||Hiroyuki Honda, Hideomi Hamasaki, Tomihiro Wakamiya, Satoshi O Suzuki, Naoki Fujii, Toru Iwaki, Loss of hnRNPA1 in ALS spinal cord motor neurons with TDP-43-positive inclusions, Neuropathology, 10.1111/neup.12153, 35, 1, 37-43, 2015.01.
||Masaaki Hokama, Sugako Oka, Julio Leon, Toshiharu Ninomiya, Hiroyuki Honda, Kensuke Sasaki, Toru Iwaki, Tomoyuki Ohara, Tomio Sasaki, Frank M. LaFerla, Yutaka Kiyohara, Yusaku Nakabeppu, Altered expression of diabetes-related genes in Alzheimer's disease brains
The Hisayama study, Cerebral Cortex, 10.1093/cercor/bht101, 24, 9, 2476-2488, 2014.01, Diabetes mellitus (DM) is considered to be a risk factor for dementia including Alzheimer's disease (AD). However, the molecular mechanism underlying this risk is not well understood. We examined gene expression profiles in postmortem human brains donated for the Hisayama study. Three-way analysis of variance of microarray data from frontal cortex, temporal cortex, and hippocampus was performed with the presence/absence of AD and vascular dementia, and sex, as factors. Comparative analyses of expression changes in the brains of AD patients and a mouse model of AD were also performed. Relevant changes in gene expression identified by microarray analysis were validated by quantitative real-time reverse-transcription polymerase chain reaction and western blotting. The hippocampi of AD brains showed the most significant alteration in gene expression profile. Genes involved in noninsulin-dependent DM and obesity were significantly altered in both AD brains and the AD mouse model, as were genes related to psychiatric disorders and AD. The alterations in the expression profiles of DM-related genes in AD brains were independent of peripheral DM-related abnormalities. These results indicate that altered expression of genes related to DM in AD brains is a result of AD pathology, which may thereby be exacerbated by peripheral insulin resistance or DM..
||Hideomi Hamasaki, Hiroyuki Honda, Satoshi Suzuki, Masaaki Hokama, Yutaka Kiyohara, Yusaku Nakabeppu, Toru Iwaki, Down-regulation of MET in hippocampal neurons of Alzheimer's disease brains, Neuropathology, 10.1111/neup.12095, 34, 3, 284-290, 2014.01, We found that mRNA of MET, the receptor of hepatocyte growth factor (HGF), is significantly decreased in the hippocampus of Alzheimer's disease (AD) patients. Therefore, we tried to determine the cellular component-dependent changes of MET expressions. In this study, we examined cellular distribution of MET in the cerebral neocortices and hippocampi of 12 AD and 11 normal controls without brain diseases. In normal brains, MET immunoreactivity was observed in the neuronal perikarya and a subpopulation of astrocytes mainly in the subpial layer and white matter. In AD brains, we found marked decline of MET in hippocampal pyramidal neurons and granule cells of dentate gyrus. The decline was more obvious in the pyramidal neurons of the hippocampi than that in the neocortical neurons. In addition, we found strong MET immunostaining in reactive astrocytes, including those near senile plaques. Given the neurotrophic effects of the HGF/MET pathway, this decline may adversely affect neuronal survival in AD cases. Because it has been reported that HGF is also up-regulated around senile plaques, β-amyloid deposition might be associated with astrocytosis through the HGF signaling pathway..
||Tomihiro Wakamiya, Satoshi Suzuki, Hideomi Hamasaki, Hiroyuki Honda, Masahiro Mizoguchi, Koji Yoshimoto, Toru Iwaki, Elevated expression of fatty acid synthase and nuclear localization of carnitine palmitoyltransferase 1C are common among human gliomas, Neuropathology, 10.1111/neup.12132, 34, 5, 465-474, 2014.01, Fatty acid synthase (FASN) and carnitine palmitoyltransferase 1C (CPT1C), a brain-specific isoform of the CPT1 family, are upregulated in certain types of cancers, including gliomas. Acetyl-CoA carboxylase (ACC) catalyzes the carboxylation of acetyl-CoA to malonyl-CoA, the rate-limiting step in fatty acid synthesis, and its phosphorylated form inhibits lipid synthesis. We examined the expression and subcellular localization of these fatty acid metabolism-related molecules in human gliomas. We performed immunostaining of two glioma cell lines (U373MG and U87MG) and 41 surgical specimens of diffuse gliomas with various histological grades (21 with the isocitrate dehydrogenase 1(IDH1) R132H mutation and 20 without the mutation). In the cultured glioma cells, CPT1C and phosphorylated ACC (p-ACC) were mainly localized to the nuclei, whereas FASN localized to the cytoplasm. In the surgical specimens, most glioma tissues showed nuclear staining for CPT1C and p-ACC, and cytoplasmic staining for FASN, regardless of the genetic status of IDH1 and the histological grade. Therefore, elevated cytoplasmic expression of FASN and nuclear localization of CPT1C are common among human diffuse gliomas, which may be regulated by the differential phosphorylation status of ACC in the cellular compartment..
||Hiroyuki Honda, R. Ishii, A. Hamano, K. Itoh, Satoshi Suzuki, S. Fushiki, M. Nakagawa, Toru Iwaki, Microsphere formation in a subtype of Creutzfeldt-Jakob disease with a V180I mutation and codon 129 MM polymorphism, Neuropathology and Applied Neurobiology, 10.1111/nan.12047, 39, 7, 844-848, 2013.12.
||Hiroyuki Honda, Kensuke Sasaki, Haruhiko Minaki, Kenta Masui, Satoshi Suzuki, Katsumi Doh-ura, Toru Iwaki, Protease-resistant PrP and PrP oligomers in the brain in human prion diseases after intraventricular pentosan polysulfate infusion, Neuropathology, 10.1111/j.1440-1789.2011.01245.x, 32, 2, 124-132, 2012.04, Intraventricular infusion of pentosan polysulfate (PPS) as a treatment for various human prion diseases has been applied in Japan. To evaluate the influence of PPS treatment we performed pathological examination and biochemical analyses of PrP molecules in autopsied brains treated with PPS (one case of sporadic Creutzfeldt-Jakob disease (sCJD, case 1), two cases of dura mater graft-associated CJD (dCJD, cases 2 and 4), and one case of Gerstmann-Sträussler-Scheinker disease (GSS, case 3). Six cases of sCJD without PPS treatment were examined for comparison. Protease-resistant PrP (PrPres) in the frontal lobe was evaluated by Western blotting after proteinase K digestion. Further, the degree of polymerization of PrP molecules was examined by the size-exclusion gel chromatography assay. PPS infusions were started 3-10 months after disease onset, but the treatment did not achieve any clinical improvements. Postmortem examinations of the treated cases revealed symmetrical brain lesions, including neuronal loss, spongiform change and gliosis. Noteworthy was GFAP in the cortical astrocytes reduced in all treated cases despite astrogliosis. Immunohistochemistry for PrP revealed abnormal synaptic deposits in all treated cases and further plaque-type PrP deposition in case 3 of GSS and case 4 of dCJD. Western blotting showed relatively low ratios of PrPres in case 2 of dCJD and case 3 of GSS, while in the treated sCJD (case 1), the ratio of PrPres was comparable with untreated cases. The indices of oligomeric PrP were reduced in one sCJD (case 1) and one dCJD (case 2). Although intraventricular PPS infusion might modify the accumulation of PrP oligomers in the brains of patients with prion diseases, the therapeutic effects are still uncertain..
||Toru Saiga, Takahisa Tateishi, Takako Torii, Nobutoshi Kawamura, Yuko Nagara, Hiroshi Shigeto, Akihiro Hashiguchi, Hiroshi Takashima, Hiroyuki Honda, Yasumasa Ohyagi, Jun-Ichi Kira, Inflammatory radiculoneuropathy in an ALS4 patient with a novel SETX mutation, Journal of Neurology, Neurosurgery and Psychiatry, 10.1136/jnnp-2012-302281, 83, 7, 763-764, 2012.01.
||Takeshi Matsuoka, Naoki Fujii, Akira Kondo, Akiko Iwaki, Toshihiro Hokonohara, Hiroyuki Honda, Kensuke Sasaki, Satoshi Suzuki, Toru Iwaki, An autopsied case of sporadic adult-onset amyotrophic lateral sclerosis with FUS-positive basophilic inclusions, Neuropathology, 10.1111/j.1440-1789.2010.01129.x, 31, 1, 71-76, 2011.02, Basophilic inclusions (BIs), which are characterized by their staining properties of being weakly argyrophilic, reactive with Nissl staining, and immunohistochemically negative for tau and transactive response (TAR) DNA-binding protein 43 (TDP-43), have been identified in patients with juvenile-onset amyotrophic lateral sclerosis (ALS) and adult-onset atypical ALS with ophthalmoplegia, autonomic dysfunction, cerebellar ataxia, or a frontal lobe syndrome. Mutations in the fused in sarcoma gene (FUS) have been reported in cases of familial and sporadic ALS, and FUS immunoreactivity has been demonstrated in basophilic inclusion body disease (BIBD), neuronal intermediate filament inclusion disease (NIFID), and atypical frontotemporal lobar degeneration with ubiquitin-positive and tau-negative inclusions (aFTLD-U). In the present study, we immunohistochemically and ultrastructurally studied an autopsy case of sporadic adult-onset ALS with numerous BIs. The patient presented with the classical clinical course of ALS since 75 years of age and died at age 79. Postmortem examination revealed that both Betz cells in the motor cortex and motor neurons in the spinal cord were affected. The substantia nigra was spared. Notably, BIs were frequently observed in the motor neurons of the anterior horns, the inferior olivary nuclei, and the basal nuclei of Meynert. BIs were immunopositive for p62, LC3, and FUS, but immunonegative for tau, TDP-43, and neurofilament. Ultrastructurally, BIs consisted of filamentous or granular structures associated with degenerated organelles with no limiting membrane. There were no Bunina bodies, skein-like inclusions, or Lewy-like inclusions. All exons and exon/intron boundaries of the FUS gene were sequenced but no mutations were identified..
||Haruhiko Minaki, Kensuke Sasaki, Hiroyuki Honda, Toru Iwaki, Prion protein oligomers in Creutzfeldt-Jakob disease detected by gel-filtration centrifuge columns
Original Article, Neuropathology, 10.1111/j.1440-1789.2009.01007.x, 29, 5, 536-542, 2009.10, Prion diseases are diagnosed by the detection of accumulation of abnormal prion protein (PrP) using immunohistochemistry or the detection of protease-resistant abnormal PrP (PrPres). Although the abnormal PrP is neurotoxic by forming aggregates, recent studies suggest that the most infectious units are smaller than the amyloid fibrils. In the present study, we developed a simplified method by applying size-exclusion gel-filtration chromatography to examine PrP oligomers without proteinase K digestion in Creutzfeldt-Jakob disease (CJD) samples, and evaluated the correlation between disease severity and the polymerization degree of PrP. Brain homogenates of human CJD and non-CJD cases were applied to the gel-filtration spin columns, and fractionated PrP molecules in each fraction were detected by western blot. We observed that PrP oligomers could be detected by the simple gel-filtration method and distinctly separated from monomeric cellular PrP (PrPc). PrP oligomers were increased according to the disease severity, accompanied by the depletion of PrPc. The separated PrP oligomers were already protease-resistant in the case with short disease duration. In the cases with quite severe pathology the oligomeric PrP reached a plateau, which may indicate that PrP molecules could mostly develop into amyloid fibrils in the advanced stages. The increase of PrP oligomers correlated with the degree of histopathological changes such as spongiosis and gliosis. The decrease of monomeric PrPc was unexpectedly obvious in the diseased cases. Dynamic changes of both oligomerization of the human PrP and depletion of normal PrPc require further elucidation to develop a greater understanding of the pathogenesis of human prion diseases..