Lysosomal malfunction accompanies alpha-synuclein aggregation in a progressive mouse model of Parkinson's disease

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 (x-synuclein in the nigral and limbic cortical neurons of treated mice. These data provide evidence that insoluble proteins, such as a-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 a-synuclein and that abundant lysosomal compartments are present to seal off the potentially toxic material. (C) 2002 Elsevier Science B.V. All rights reserved.