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. © 2014 International Parkinson and Movement Disorder Society

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BackgroundThe histological hallmark of multiple system atrophy (MSA) is the presence of filamentous aggregations of phosphorylated α-synuclein in oligodendrocytes, referred to as glial cytoplasmic inclusions (GCIs). Although GCIs can occur widely in the central nervous system, accumulation of phosphorylated α-synuclein in Schwann cells has not been reported in MSA. We immunohistochemically examined the cranial and spinal nerves, peripheral ganglia and visceral autonomic nervous system of patients with MSA (n = 14) and control subjects (n = 20).ResultsIn MSA, accumulation of phosphorylated α-synuclein was found in the cytoplasm of Schwann cells. These Schwann cell cytoplasmic inclusions (SCCIs) were also immunopositive for ubiquitin and p62. SCCIs were found in 12 of 14 patients with MSA (85.7 %). They were most frequent in the anterior nerve of the sacral cord and, to a lesser extent, in the cranial nerves (oculomotor, glossopharyngeal-vagus and hypoglossal nerves), and spinal and sympathetic ganglia. SCCIs were rarely found in the visceral organs. Immunoelectron microscopy demonstrated that the SCCIs consisted of abnormal filaments, 15–20 nm in diameter. No such inclusions were found in controls.ConclusionThe present findings indicate that Schwann cells are also involved in the disease process of MSA.

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.

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.