| Parkinson's disease (PD) is a neurodegenerative disorder characterized by resting tremor and postural rigidity. The progressive loss of dopaminergic neurons in the substantia nigra pars compacta is the key pathologic feature underlying these symptoms. Mutations in the synaptic protein α-synuclein are linked to autosomal-dominant PD. Moreover, α-synuclein is also a major component of Lewy bodies (LBs) found in idiopathic PD. We modelled PD in Drosophila by directing the expression of asynuclein to dopaminergic neurons. Expression of α-synuclein resulted in both the age-dependent degeneration of 50% of the dopaminergic neurons in the dorsomedial clusters of the fly brain and the formation of LB-like aggregates. As a genetic organism, Drosophila is an ideal system in which to study modifiers of α-synuclein toxicity with potential therapeutic relevance. We therefore tested whether the molecular chaperone Hsp70 could protect against α-synuclein toxicity.; Transgenic expression of Hsp70 fully protected against the toxicity of α-synuclein to dopaminergic neurons. Furthermore, compromising endogenous chaperone activity accelerated α-synuclein-mediated neurodegeneration. Hsp70 and other chaperones also found to localize to LBs in postmortem PD brain tissue and to LB-like aggregates in the brains of transgenic α-synuclein flies. Thus it appears that chaperone activity may be altered in PD patients and contributes to the toxicity of α-synuclein.; We next examined whether pharmacological enhancement of chaperone activity might also protect against α-synuclein toxicity. Geldanamycin (GA) is an antibiotic that inhibits the activity of Hsp90 which negatively regulates heat shock factor (HSF), the transcriptional activator of Hsp70 and other chaperones. Treatment of adult flies with GA fully suppressed the toxicity of α-synuclein. Using a temperature-sensitive null allele of HSF, we found that GA-mediated neuroprotection was fully dependent upon HSF activity; genetic elimination of HSF activity abrogated the drug's cytoprotective activity. Finally, we determined that other pathways modified by Hsp90 were not responsible for neuroprotection by GA. Through these studies, we have shown that enhancement of chaperone activity, both genetically and pharmacologically, is a potent mitigator of α-synuclein toxicity in Drosophila. We propose that targeted enhancement of chaperone pathways should be further investigated as a cytoprotective treatment for PD and related neurodegenerative disorders. |
