Multiple system atrophy: cellular and molecular pathology

Abstract

Multiple system atrophy is an adult onset neurodegenerative disease, featuring parkinsonism, ataxia, and autonomic failure, in any combination. The condition is relentlessly progressive and responds poorly to treatment. Death occurs on average six to seven years after the onset of symptoms. No familial cases of multiple system atrophy have been reported, and no environmental factors have been robustly implicated as aetiological factors. However, analytical epidemiological studies are hampered because the condition is relatively rare. The discovery of the glial cytoplasmic inclusion (GCI) in 1989 helped to define multiple system atrophy as a clinicopathological entity, and drew attention to the prominent, if not primary, role played by the oligodendrocyte in the pathogenesis of the condition. Subsequently, GCIs were shown to be positive for alpha-synuclein, with immunostaining for this protein indicating that white matter pathology was more widespread than had previously been recognised. The presence of alpha-synuclein in GCIs provides a link with Parkinson's disease, dementia with Lewy bodies, and neurodegeneration with brain iron accumulation, type 1 (or Hallervorden-Spatz syndrome), in which alpha-synuclein is also found within Lewy bodies. This has led to the term "synucleinopathy" to embrace this group of conditions. The GCIs of multiple system atrophy contain a range of other cytoskeletal proteins. It is unknown how fibrillogenesis occurs, and whether there is primary oligodendrocytic dysfunction, which then disrupts the neurone/axon as a consequence of the glial pathology, or whether the oligodendrocytic changes merely represent an epiphenomenon. Further research into this devastating condition is urgently needed to improve our understanding of the pathogenesis, and also to produce new treatment approaches.

Figure 1

α-Synuclein pathology in multiple system atrophy. (A) Glial cytoplasmic inclusions (GCls) (arrows) in cerebellar white matter with cerebellar granule cells in the lower right corner. (B) Neuronal cytoplasmic inclusions (NCIs) (double arrows) and an early formation of a neuronal nuclear inclusion (NNI) (triple arrow) in neurones of pontine nuclei with neurites in the neuropil (arrowheads). (C) A GCI (arrow) and the early formation of an NCI (double arrow) and NNI (triple arrow) in a neurone of the pontine nuclei with neurites in the neuropil (arrowheads). (D) A GCI (arrow) and an NNI (triple arrow) in the pontine nuclei. Immunohistochemistry was performed using monoclonal antibodies to α-synuclein (Novocastra Laboratories, Newcastle upon Tyne, UK) on formalin fixed, paraffin wax embedded sections that had been pretreated with formic acid; Vectastain Elite ABC peroxidase kit (Vector, Peterborough, UK); DAB; Haematoxylin counterstain. Scale bars in A to D, 30 μm.