In 1999, Warrick et al. showed that the molecular chaperone Hsp70 could suppress neurodegeneration mediated by polyQ expansions in a protein associated with spinocerebellar ataxia. Now research from the same laboratory, directed by Nancy Bonini, University of Pennsylvania, suggests that molecular chaperones may also ameliorate neurodegeneration in Parkinson's disease (PD).
Published online in yesterday's ScienceExpress, the work uses a Drosophila model of PD developed by Mel Feany (see related news item), in which expression of human α-synuclein is driven by the fly DOPA decarboxylase promoter. By 20 days of age, flies expressing the human transgene had lost up to half of their neurons in the dorsomedial and dorsolateral-1 dopaminergic clusters of the brain. Coexpression of human Hsp70 markedly protected the flies such that 20 day-old flies showed no neuronal loss.
This fly model shows a gradual increase in the number of α-synuclein-containing inclusion bodies, and this was unaltered in flies also expressing Hsp70. In addition, Drosophila Hsp70 was found in the Lewy body-like inclusions, suggesting that it may interact with human α-synuclein. Coexpression of α-synuclein with a dominant-negative mutant of Hsc4, the major Drosophila Hsp70 protein, resulted in accelerated loss of dopaminergic neurons, strengthening the case for interaction of the chaperone with the human protein. "This work is nicely done and will be of great interest to those in the field," comments Mel Feany of Brigham and Women's Hospital, Boston.
Overall the results suggest that chaperone activity may be critical for the viability of dopaminergic neurons challenged by aberrant α-synuclein metabolism.—Tom Fagan
- Warrick JM, Chan HY, Gray-Board GL, Chai Y, Paulson HL, Bonini NM. Suppression of polyglutamine-mediated neurodegeneration in Drosophila by the molecular chaperone HSP70. Nat Genet. 1999 Dec;23(4):425-8. PubMed.
- Auluck PK, Chan HY, Trojanowski JQ, Lee VM, Bonini NM. Chaperone suppression of alpha-synuclein toxicity in a Drosophila model for Parkinson's disease. Science. 2002 Feb 1;295(5556):865-8. PubMed.