||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..
||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..
||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.
||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..