Neuropathology

Neuropathologically, MSA is characterized by selective neuronal loss and gliosis predominantly affecting substantia nigra and striatum (striatonigral degeneration, SND) as well as olivopontocerebellar (olivopontocerebellar atrophy, OPCA) pathways and the intermediolateral cell column of the spinal cord. Glial inclusion formation is a prominent feature of MSA pathology and has therefore been added to the diagnostic criteria of definite MSA. Although inclusions have been described in 5 cellular sites, i. e. in oligodendroglial and neuronal cytoplasm and nuclei as well as in axons, glial cytoplasmic inclusions (GCIs) appear to represent the subcellular hallmark lesion of MSA. Their distribution selectively involves basal ganglia, supplementary and primary motor cortex, the reticular formation, basis pontis, the middle cerebellar peduncles and the cerebellar white matter. The origin of GCIs remains mysterious. GCIs are argyrophilic and half moon, oval or conical in shape. They consist of 20 to 30 nm diameter filaments and contain the classical cytoskeletal antigens, ubiquitin and tau. The tau profile of MSA was shown to be different from tau pattern in Alzheimer´s disease, PSP and CBD, more closely resembling normal adult tau. Furthermore, alpha-synuclein, a presynaptic protein which is affected by point mutations in some families with autosomal dominant PD and which is present in Lewy bodies, has also been observed in both neuronal and glial cytoplasmic inclusions in MSA brains. This has led to the assumption that MSA belongs to the synucleinopathies like PD and dementia with Lewy bodies. Alpha-synuclein is a 140 amino acid protein that is abundantly expressed in the brain, typically enriched at presynaptic terminals and might be implicated in the process of lifelong learning and memory function. The exact functions of alpha-synuclein in the CNS, as well as its subcellular distribution, remain unknown up to now. However, there is experimental evidence from mutant mice suggesting that alpha-synuclein is a presynaptic activity-dependent negative regulator of dopamine transmission. It is established that the expression of this protein is exclusively found in the soluble fraction of the neuronal cytoplasm, while in MSA brains alpha-synuclein forms insoluble aggregates. Whether the aggregation of alpha-synuclein is induced by some other factor(s), or whether it is the primary trigger of MSA pathology is unknown. Abnormalities in the alpha-synuclein gene have also been evaluated in MSA, since A53T and A30P mutations have been reported in some families with autosomal dominant PD. However, a detailed nucleotide sequence analysis of the alpha-synuclein gene in 11 confirmed cases of MSA has suggested that mutations are not likely to contribute to the pathogenesis of MSA. Other questions that remain to be elucidated are to what extent alpha-synuclein is normally expressed by oligodendrocytes and whether the formation of GCIs precedes or follows neuronal degeneration.