Extensive distribution of glial cytoplasmic inclusions in an autopsied case of multiple system atrophy with a prolonged 18‐year clinical course

Masui, Kenta; Nakata, Yoshio; Fujii, Naoki; Iwaki, Toru

doi:10.1111/j.1440-1789.2011.01222.x

Cited by 19 publications

(14 citation statements)

References 28 publications

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“…This case manifesting only mild clinical symptoms was recently suggested to represent “early MSA” rather than “minimal change” MSA . Rare cases of MSA‐P with slow progression and prolonged survival were considered an uncommon “benign” subgroup, whereas another case with prolonged clinical course of 18 years showed extensive distribution of GCIs in wide CNS areas . A subgroup with severe temporal atrophy showed numerous NCIs, particularly in the limbic system .…”

Section: Rare Subtypes Of Msamentioning

confidence: 95%

Neuropathology of multiple system atrophy: New thoughts about pathogenesis

Jellinger¹

2014

Movement Disorders

154

135

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Multiple system atrophy (MSA) is a fatal adult-onset neurodegenerative disorder of uncertain etiology, clinically manifesting with autonomic failure associated with parkinsonism, cerebellar dysfunction, and pyramidal signs in variable combination. The pathological process affects central autonomic, striatonigral, and olivopontocerebellar systems. These show varying degrees of neurodegeneration and underlie the stratification of the heterogenous disorder into MSA-P and MSA-C clinical variants, which correlate to the morphologic phenotypes of striatonigral degeneration and olivopontocerebellar atrophy (MSA-C). The lesions are not limited to these most consistently and severely affected systems but may involve many other parts of the central, peripheral, and autonomic nervous systems, underpinning the multisystem character of MSA. The histological core feature are glial cytoplasmic inclusions (GCIs, Papp-Lantos bodies) in all types of oligodendroglia that contain aggregates of misfolded α-Synuclein (α-Syn). In addition to the ectopic appearance of α-Syn in oligodendrocytes and other cells, oxidative stress, proteasomal and mitochondrial dysfunction, excitotoxiciy, neuroinflammation, metabolic changes, and energy failure are important contributors to the pathogenesis of MSA, as shown by various neurotoxic and transgenic animal models. Although the basic mechanisms of α-Syn-triggered neurodegeneration are not completely understood, neuron-to-oligodendrocyte transfer of α-Syn by prion-like spreading, inducing oligodendroglial and myelin dysfunction associated with chronic neuroinflammation, are suggested finally to lead to a system-specific pattern of neurodegeneration.

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Section: Rare Subtypes Of Msamentioning

confidence: 95%

Neuropathology of multiple system atrophy: New thoughts about pathogenesis

Jellinger¹

2014

Movement Disorders

154

135

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“…Many of these patients developed motor fluctuations and levodopa-induced choreiform dyskinesias, which would have indicated deep brain stimulation, not recommended for MSA patients [ 320, 321 ]. These rare long surviving patients with MSA-P were considered “benign” forms [ 43 ], whereas other cases with clinical course of 18 years revealed extensive distribution of GCIs in CNS [ 322 ]. A non-motor variant of pathologically confirmed MSA showed neither parkinsonism nor cerebellar symptoms [ 323 ].…”

Section: Neuropathologymentioning

confidence: 99%

Multiple System Atrophy: An Oligodendroglioneural Synucleinopathy1

Jellinger¹

2018

JAD

150

142

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Multiple system atrophy (MSA) is an orphan, fatal, adult-onset neurodegenerative disorder of uncertain etiology that is clinically characterized by various combinations of parkinsonism, cerebellar, autonomic, and motor dysfunction. MSA is an α-synucleinopathy with specific glioneuronal degeneration involving striatonigral, olivopontocerebellar, and autonomic nervous systems but also other parts of the central and peripheral nervous systems. The major clinical variants correlate with the morphologic phenotypes of striatonigral degeneration (MSA-P) and olivopontocerebellar atrophy (MSA-C). While our knowledge of the molecular pathogenesis of this devastating disease is still incomplete, updated consensus criteria and combined fluid and imaging biomarkers have increased its diagnostic accuracy. The neuropathologic hallmark of this unique proteinopathy is the deposition of aberrant α-synuclein in both glia (mainly oligodendroglia) and neurons forming glial and neuronal cytoplasmic inclusions that cause cell dysfunction and demise. In addition, there is widespread demyelination, the pathogenesis of which is not fully understood. The pathogenesis of MSA is characterized by propagation of misfolded α-synuclein from neurons to oligodendroglia and cell-to-cell spreading in a “prion-like” manner, oxidative stress, proteasomal and mitochondrial dysfunction, dysregulation of myelin lipids, decreased neurotrophic factors, neuroinflammation, and energy failure. The combination of these mechanisms finally results in a system-specific pattern of neurodegeneration and a multisystem involvement that are specific for MSA. Despite several pharmacological approaches in MSA models, addressing these pathogenic mechanisms, no effective neuroprotective nor disease-modifying therapeutic strategies are currently available. Multidisciplinary research to elucidate the genetic and molecular background of the deleterious cycle of noxious processes, to develop reliable biomarkers and targets for effective treatment of this hitherto incurable disorder is urgently needed.

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“…Despite the primarily oligodendrocytic accumulation of α‐syn, MSA patients also display considerable neuronal loss in the striatum, cerebellum, brainstem and cortex, accompanied by astrogliosis, microgliosis and myelin loss (173, 182). Interestingly, a recent study has reported p62 immunoreactivity (a ubiquitin‐associated autophagy substrate) in GCIs of a MSA patient (109) highlighting the possibility that autophagocytic alterations may also play a role in this disorder.…”

Section: Alterations In Autophagy In α‐Synucleinopathiesmentioning

confidence: 99%

Autophagy in Dementias

et al. 2011

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Dementias are a varied group of disorders typically associated with memory loss, impaired judgment and/or language and by symptoms affecting other cognitive and social abilities to a degree that interferes with daily functioning. Alzheimer’s disease (AD) is the most common cause of a progressive dementia, followed by dementia with Lewy bodies (DLB), frontotemporal dementia (FTD), vascular dementia (VaD) and HIV associated neurocognitive disorders (HAND). The pathogenesis of this group of disorders has been linked to the abnormal accumulation of proteins in the brains of affected individuals, which in turn has been related to deficits in protein clearance. Autophagy is a key cellular protein clearance pathway with proteolytic cleavage and degradation via the ubiquitin-proteasome pathway representing another important clearance mechanism. Alterations in the levels of autophagy and the proteins associated with the autophagocytic pathway have been reported in various types of dementias. This review will examine recent literature across these disorders and highlight a common theme of altered autophagy across the spectrum of the dementias.

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Extensive distribution of glial cytoplasmic inclusions in an autopsied case of multiple system atrophy with a prolonged 18‐year clinical course

Cited by 19 publications

References 28 publications

Neuropathology of multiple system atrophy: New thoughts about pathogenesis

Neuropathology of multiple system atrophy: New thoughts about pathogenesis

Multiple System Atrophy: An Oligodendroglioneural Synucleinopathy1

Autophagy in Dementias

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