The neural chaperone proSAAS blocks α-synuclein fibrillation and neurotoxicity

Emerging evidence strongly suggests that chaperone proteins are cytoprotective in neurodegenerative proteinopathies involving protein aggregation; for example, in the accumulation of aggregated α-synuclein into the Lewy bodies present in Parkinson’s disease. Of the various chaperones known to be ass...

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Published in:Proceedings of the National Academy of Sciences - PNAS 2016-08, Vol.113 (32), p.E4708-E4715
Main Authors: Jarvela, Timothy S., Lam, Hoa A., Helwig, Michael, Lorenzen, Nikolai, Otzen, Daniel E., McLean, Pamela J., Maidment, Nigel T., Lindberg, Iris
Format: Article
Language:English
Subjects:
alpha-Synuclein - metabolism
alpha-Synuclein - toxicity
Animals
Biological Sciences
Cells, Cultured
Humans
Lewy Bodies - metabolism
Neuropeptides - chemistry
Neuropeptides - physiology
Neurotoxicity Syndromes - prevention & control
PNAS Plus
Protein Aggregates
Protein Multimerization
Rats
Substantia Nigra - metabolism
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Summary:Emerging evidence strongly suggests that chaperone proteins are cytoprotective in neurodegenerative proteinopathies involving protein aggregation; for example, in the accumulation of aggregated α-synuclein into the Lewy bodies present in Parkinson’s disease. Of the various chaperones known to be associated with neurodegenerative disease, the small secretory chaperone known as proSAAS (named after four residues in the amino terminal region) has many attractive properties. We show here that proSAAS, widely expressed in neurons throughout the brain, is associated with aggregated synuclein deposits in the substantia nigra of patients with Parkinson’s disease. Recombinant proSAAS potently inhibits the fibrillation of α-synuclein in an in vitro assay; residues 158–180, containing a largely conserved element, are critical to this bioactivity. ProSAAS also exhibits a neuroprotective function; proSAAS-encoding lentivirus blocks α-synuclein-induced cytotoxicity in primary cultures of nigral dopaminergic neurons, and recombinant proSAAS blocks α-synuclein–induced cytotoxicity in SH-SY5Y cells. Four independent proteomics studies have previously identified proSAAS as a potential cerebrospinal fluid biomarker in various neurodegenerative diseases. Coupled with prior work showing that proSAAS blocks β-amyloid aggregation into fibrils, this study supports the idea that neuronal proSAAS plays an important role in proteostatic processes. ProSAAS thus represents a possible therapeutic target in neurodegenerative disease.
ISSN:0027-8424
1091-6490
DOI:10.1073/pnas.1601091113