天美传媒

Abstract

Multiple system atrophy (MSA) is a rare, rapidly progressive neurodegenerative disorder of uncertain aetiology, presenting
with autonomic failure variably combined with parkinsonism, cerebellar dysfunction, and pyramidal signs. The
pathological process affects central autonomic, striatonigral and olivopontocerebellar systems showing varying degrees of
degeneration that underlie the stratification of the heterogenous disorder into two major clinical variants correlating to the
morphological phenotypes of striatonigral degeneration (SND) (MSA-P) and olivopontocerebellar atrophy (MSA-C). The
lesions are not limited to these most consistently and severely affected systems, but may involve other parts of the central,
peripheral and autonomic nervous system, confirming the multisystem character of MSA. The histological core feature
are distinctive glial cytoplasmic inclusions (GCI, Papp-Lantos bodies) containing misfolded α-synuclein (αSyn) within
oligodendroglia cells that are required for the postmortem diagnosis of definite MSA. In addition to ectopic deposition
of modified αSyn in oligodendroglia and other cells/tissues, oxidative stress, proteasomal and mitochondrial dysfunction,
dysregulation of myelin lipids, impairment of oligodendrocyte progenitor cells, and energy failure are important contributors
to the pathogenesis of this unique proteinopathy, as shown by various transgenic and other animal models. Although the basic
mechanisms of αSyn-triggered gliopathy are not fully understood, neuron-to-oligodendrocyte transfer of αSyn and “prion-like”
spreading of synucleinopathy inducing oligodendroglial and myelin dysfunction associated with chronic neuroinflammation.
These lesions and recently described frequent occurrence of neuronal inclusions in many regions of MSA brain are finally
leading to a system-specific pattern of neurodegeneration, which may act as an emerging template for cause-directed and
disease-modifying therapies of MSA.

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