Tomoya Kon

Morphologic changes of dendritic spines of striatal neurons in the levodopa-induced dyskinesia model.

Maladaptive plasticity at corticostriatal synapses plays an important role in the development of levodopa‐induced dyskinesia. Recently, it has been shown that synaptic plasticity is closely linked to morphologic changes of dendritic spines. To evaluate morphologic changes of dendritic spines of two types of striatal medium spiny neurons, which project to the internal segment of globus pallidus or the external segment of globus pallidus, in the levodopa‐induced dyskinesia model, we used 6‐hydroxydopamine‐lesioned rats chronically treated with levodopa. Dendritic spines were decreased and became enlarged in the direct pathway neurons of the model of levodopa‐induced dyskinesia. The same levodopa treatment to normal rats, in which no dyskinesia was observed, also induced enlargement of dendritic spines, but not a decrease in density of spines in the direct pathway neurons. These results suggest that a loss and enlargement of dendritic spines in the direct pathway neurons plays important roles in the development of levodopa‐induced dyskinesia.

Accumulation of the sigma‐1 receptor is common to neuronal nuclear inclusions in various neurodegenerative diseases

The sigma‐1 receptor (SIGMAR1) is now known to be one of the endoplasmic reticulum (ER) chaperones, which participate in the degradation of misfolded proteins in cells via the ER‐related degradation machinery linked to the ubiquitin‐proteasome pathway. Mutations of the SIGMAR1 gene are implicated in the pathogenesis of familial frontotemporal lobar degeneration and motor neuron disease. Involvement of ER dysfunction in the formation of inclusion bodies in various neurodegenerative diseases has also become evident. We performed immunohistochemical staining to clarify the localization of SIGMAR1 in the brains of patients with neurodegenerative disorders, including trans‐activation response DNA protein 43 (TDP‐43) proteinopathy, tauopathy, α‐synucleinopathy, polyglutamine disease and intranuclear inclusion body disease (INIBD). Double‐immunocytofluorescence and Western blot analyses of cultured cells were also performed to investigate the role of SIGMAR1 using a specific exportin 1 inhibitor, leptomycin B and an ER stress inducer, thapsigargin. SIGMAR1 was consistently shown to be co‐localized with neuronal nuclear inclusions in TDP‐43 proteinopathy, five polyglutamine diseases and INIBD, as well as in intranuclear Marinesco bodies in aged normal controls. Cytoplasmic inclusions in neurons and glial cells were unreactive for SIGMAR1. In cultured cells, immunocytofluorescent study showed that leptomycin B and thapsigargin were shown to sequester SIGMAR1 within the nucleus, acting together with p62. This finding was also supported by immunoblot analysis. These results indicate that SIGMAR1 might shuttle between the nucleus and the cytoplasm. Neurodegenerative diseases characterized by neuronal nuclear inclusions might utilize the ER‐related degradation machinery as a common pathway for the degradation of aberrant proteins.

ALS-associated protein FIG4 is localized in Pick and Lewy bodies, and also neuronal nuclear inclusions, in polyglutamine and intranuclear inclusion body diseases.

FIG4 is a phosphatase that regulates intracellular vesicle trafficking along the endosomal‐lysosomal pathway. Mutations of FIG4 lead to the development of Charcot‐Marie‐Tooth disease type 4J and amyotrophic lateral sclerosis (ALS). Moreover, ALS‐associated proteins (transactivation response DNA protein 43 (TDP‐43), fused in sarcoma (FUS), optineurin, ubiquilin‐2, charged mutivesicular body protein 2b (CHMP2B) and valosin‐containing protein) are involved in inclusion body formation in several neurodegenerative diseases. Using immunohistochemistry, we examined the brains and spinal cords of patients with various neurodegenerative diseases, including sporadic TDP‐43 proteinopathy (ALS and frontotemporal lobar degeneration). TDP‐43 proteinopathy demonstrated no FIG4 immunoreactivity in neuronal inclusions. However, FIG4 immunoreactivity was present in Pick bodies in Picks disease, Lewy bodies in Parkinsons disease and dementia with Lewy bodies, neuronal nuclear inclusions in polyglutamine and intranuclear inclusion body diseases, and Marinesco and Hirano bodies in aged control subjects. These findings suggest that FIG4 is not incorporated in TDP‐43 inclusions and that it may have a common role in the formation or degradation of neuronal cytoplasmic and nuclear inclusions in several neurodegenerative diseases.

FUS immunoreactivity of neuronal and glial intranuclear inclusions in intranuclear inclusion body disease

F. Mori, K. Tanji, T. Kon, S. Odagiri, M. Hattori, Y. Hoshikawa, C. Kono, K. Yasui, S. Yokoi, Y. Hasegawa, M. Yoshida and K. Wakabayashi (2012) Neuropathology and Applied Neurobiology38, 322–328

Giant cell polymyositis and myocarditis associated with myasthenia gravis and thymoma.

We describe an unusual case of myasthenia gravis. Our patient had been diagnosed as having myasthenia gravis with thymoma at the age of 64 years, and died of acute respiratory failure at the age of 80 years. Post mortem examination revealed CD8‐positive lymphocytic infiltration with numerous giant cells in the skeletal muscles and myocardium. Immunohistochemical and ultrastructural studies revealed that there were two types of giant cells: histiocytic and myocytic in origin. Furthermore, both types of giant cells were immunopositive for proteins implicated in the late endosome and lysosome‐protease systems, suggesting that endocytosis may be the key mechanism in the formation of giant cells. The present case, together with a few similar cases reported previously, may represent a particular subset of polymyositis, that is, giant cell polymyositis and myocarditis associated with myasthenia gravis and thymoma.

Accumulation of phosphorylated α-synuclein in subpial and periventricular astrocytes in multiple system atrophy of long duration

The histological hallmark of multiple system atrophy (MSA) is accumulation of phosphorylated α‐synuclein in oligodendrocytes. However, it is uncertain whether phosphorylated α‐synuclein accumulates in astrocytes of MSA patients. We immunohistochemically examined the frontal and temporal lobes, basal ganglia, cerebellum, brainstem and spinal cord of patients with MSA (n = 15) and Lewy body disease (n = 20), and also in control subjects (n = 20). Accumulation of abnormally phosphorylated and aggregated α‐synuclein was found in subpial and periventricular astrocytes in six of the 15 patients with MSA (40%). The structures were confined to the subpial surface of the ventro‐lateral part of the spinal cord and brainstem, as well as the subependymal region of the lateral ventricles. They were not visualized by Gallyas‐Braak staining, and were immunonegative for ubiquitin and p62. Immunoelectron microscopy revealed that the phosphorylated α‐synuclein‐immunoreactive structures in astrocytes were non‐fibrillar and associated with granular and vesicular structures. The extent of phosphorylated α‐synuclein‐immunoreactive astrocytes was correlated with disease duration. No such structures were found in Lewy body disease or controls. Accumulation of phosphorylated α‐synuclein can occur in subpial and periventricular astrocytes in patients with MSA, especially in those with a long disease duration.

An autopsy case of preclinical multiple system atrophy (MSA‐C)

Multiple system atrophy (MSA) is divided into two clinical subtypes: MSA with predominant parkinsonian features (MSA‐P) and MSA with predominant cerebellar dysfunction (MSA‐C). We report a 71‐year‐old Japanese man without clinical signs of MSA, in whom post mortem examination revealed only slight gliosis in the pontine base and widespread occurrence of glial cytoplasmic inclusions in the central nervous system, with the greatest abundance in the pontine base and cerebellar white matter. Neuronal cytoplasmic inclusions (NCIs) and neuronal nuclear inclusions (NNIs) were almost restricted to the pontine and inferior olivary nuclei. It was noteworthy that most NCIs were located in the perinuclear area, and the majority of NNIs were observed adjacent to the inner surface of the nuclear membrane. To our knowledge, only four autopsy cases of preclinical MSA have been reported previously, in which neuronal loss was almost entirely restricted to the substantia nigra and/or putamen. Therefore, the present autopsy case of preclinical MSA‐C is considered to be the first of its kind to have been reported. The histopathological features observed in preclinical MSA may represent the early pattern of MSA pathology.

Effects of duloxetine on motor and mood symptoms in Parkinson's disease: An open-label clinical experience

• Serotonin and norepinephrine transporters are capable of dopamine reuptake in the parkinsonian striatum.

Effects of liver transplantation and tafamidis in hereditary transthyretin amyloidosis caused by transthyretin Leu55Pro mutation: a case report

Hereditary transthyretin amyloid (ATTR) amyloidosis owing to a rare mutation which changes from leucine to proline at transthyretin (TTR) gene position 55 (Leu55Pro), has been reported as aggressiv...

Abnormal tau deposition in neurons, but not in glial cells in the cerebral tissue surrounding arteriovenous malformation

We report an autopsy case of arteriovenous malformation (AVM) of the right frontal lobe in a 50‐year‐old man, in whom post mortem examination revealed massive tau deposition in the affected cerebral cortex. The patient was diagnosed as having AVM at the age of 21 years, and died of unknown cause at the age of 50 years. Immunostaining with anti‐phosphorylated tau antibody (AT8) revealed many NFTs and neuropil threads, but not glial tau accumulation, in the right frontal cortex surrounding the AVM. The NFTs and neuropil threads contained both 3‐repeat and 4‐repeat tau. Ultrastructurally, the NFTs consisted of paired helical filaments. In the other brain areas, a few NFTs were found in the parahippocampal gyrus. There was no amyloid deposition in the brain. A variety of disease conditions, including brain tumor, viral encephalitis, angioma and cervical spondylotic myelopathy, have been reported to show Alzheimer‐type NFTs. The present findings indicate that abnormal tau deposition can occur in neurons, but not in glial cells, of the affected cerebral cortex surrounding AVM.