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 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.
Meredith
G E
GE
Department 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
Totterdell
S
S
Petroske
E
E
Santa Cruz
K
K
Callison
R C
RC
Lau
Y-S
YS
D015632:1-Methyl-4-phenyl-1,2,3,6-tetrahydropyridine / Q000494:pharmacology*; D000818:Animals; D016923:Cell Death; D002540:Cerebral Cortex / Q000187:drug effects / Q000378:metabolism / Q000648:ultrastructure; D015259:Dopamine Agents / Q000494:pharmacology*; D015870:Gene Expression; D006801:Humans; D002479:Inclusion Bodies / Q000378:metabolism / Q000648:ultrastructure; D008062:Lipofuscin / Q000378:metabolism; D008247:Lysosomes / Q000378:metabolism* / Q000648:ultrastructure; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D023421:Models, Animal; D009419:Nerve Tissue Proteins / Q000187:drug effects / Q000235:genetics / Q000378:metabolism* / Q000648:ultrastructure; D009474:Neurons / Q000187:drug effects / Q000378:metabolism / Q000648:ultrastructure; D010300:Parkinson Disease / Q000378:metabolism*; D011339:Probenecid / Q000494:pharmacology; D051843:Synucleins; D013997:Time Factors; D025801:Ubiquitin / Q000187:drug effects / Q000378:metabolism; D014528:Uricosuric Agents / Q000494:pharmacology; D051844:alpha-Synuclein
D015259:Dopamine Agents; D008062:Lipofuscin; D009419:Nerve Tissue Proteins; C497604:SNCA protein, human; C497605:Snca protein, mouse; D051843:Synucleins; D025801:Ubiquitin; D014528:Uricosuric Agents; D051844:alpha-Synuclein; D015632:1-Methyl-4-phenyl-1,2,3,6-tetrahydropyridine; D011339:Probenecid