Abstract Body

Many neurodegenerative disorders contain neuropathological lesions composed of aggregates of insoluble α-synuclein protein - primary α-synucleinopathies (idiopathic Parkinson's disease (PD), dementia with Lewy bodies (DLB) and multiple system atrophy (MSA) versus secondary α-synucleinopathies (genetic Alzheimer’s disease, lysosomal storage disorders, etc.). In Lewy body disorders astrocytes accumulate α-synuclein, but do not increase their expression of GFAP (definition of reactivity) or many other astrocytic proteins. The damage-associated molecular pattern protein S100B that is secreted by astrocytes is significantly increased in patients with PD, and astrocytes in regions accumulating Lewy pathologies also have increased intracellular α-synuclein. The astrocyte type affected are the grey matter protoplasmic astrocytes whose endfeet form part of the tripartite synapse in addition to the blood-brain barrier. The regional increase in α-synuclein in protoplasmic astrocytes parallels the stages of Lewy body accumulation in Lewy body diseases, with more astrocytes involved than neurons. While neurons but not astrocytes also accumulate α-synuclein in MSA, regional degeneration is related to oligodendroglial cytoplasmnic inclusions (GCIs) rather than neuronal α-synuclein accumulation. The oligodendroglia protein, myelin basic protein (MBP), is reduced in MSA in association with an increase in degraded MBP and an accumulation of p25α and α-synuclein in enlarged cell bodies. There is also a reduction in lipids associated with myelin and an increase in the lipid transporter ABCA8. Oligodendroglial precursors increase their relative numbers in the white matter affected in MSA. These comparisons show that glial accumulation of α-synuclein differentiate Lewy body diseases from MSA, with protoplasmic astrocytes that contact neuronal synapses and cell bodies affected in Lewy body diseases, while oligodendroglia that contact neuronal axons affected in MSA.