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Studying Pre-formed Fibril Induced α-Synuclein Accumulation in Primary Embryonic Mouse Midbrain Dopamine Neurons
Published on: August 16, 2020
Lysosomal malfunction accompanies alpha-synuclein aggregation in a progressive mouse model of Parkinson's disease
G E Meredith1, S Totterdell, E Petroske
1Department of Cellular and Molecular Pharmacology, Chicago Medical School, Finch University of Health Sciences, 3333 Green Bay Road, North Chicago, IL 60064, USA. gloria.meredith@finchcms.edu
Abstract:
We have detected granular and filamentous inclusions that are alpha-synuclein- and ubiquitin-immunoreactive in the cytoplasm of dopaminergic and cortical neurons of C57/black mice treated chronically with 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP) and probenecid. The immunoreactive aggregates only become evident several weeks after large-scale dopaminergic cell death and a downregulation of alpha-synuclein gene expression. Numerous lipofuscin granules accumulate alpha-synuclein in the nigral and limbic cortical neurons of treated mice. These data provide evidence that insoluble proteins, such as alpha-synuclein, build up as granular and filamentous inclusions in dopaminergic neurons that survive the initial toxic MPTP insult. They further suggest that defective protein degradation rather than altered gene expression underlies deposition of alpha-synuclein and that abundant lysosomal compartments are present to seal off the potentially toxic material.
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