Mechanisms of suppression of α-synuclein neurotoxicity by geldanamycin in Drosophila

被引:167
作者
Auluck, PK
Meulener, MC
Bonini, NM
机构
[1] Univ Penn, Sch Med, Philadelphia, PA 19104 USA
[2] Univ Penn, Howard Hughes Med Inst, Philadelphia, PA 19104 USA
[3] Univ Penn, Dept Biol, Philadelphia, PA 19104 USA
[4] Univ Penn, Dept Neurosci, Philadelphia, PA 19104 USA
关键词
D O I
10.1074/jbc.M412106200
中图分类号
Q5 [生物化学]; Q7 [分子生物学];
学科分类号
071010 ; 081704 ;
摘要
Parkinson's disease is a common neurodegenerative disease characterized by the loss of dopaminergic neurons in the substantia nigra pars compacta and the accumulation of the protein alpha-synuclein into aggregates called Lewy bodies and Lewy neurites. Parkinson's disease can be modeled in Drosophila where directed expression of alpha-synuclein induces compromise of dopaminergic neurons and the formation of Lewy body-like aggregates. The molecular chaperone Hsp70 protects cells from the deleterious effects of alpha-synuclein, indicating a potential therapeutic approach to enhance neuron survival in Parkinson's disease. We have now investigated the molecular mechanisms by which the drug geldanamycin protects neurons against alpha-synuclein toxicity. Our studies show that geldanamycin sensitizes the stress response within normal physiological parameters to enhance chaperone activation, offering protection against alpha-synuclein neurotoxicity. Further, geldanamycin uncouples neuronal toxicity from Lewy body and Lewy neurite formation such that dopaminergic neurons are protected from the effects of alpha-synuclein expression despite the continued presence of (and even increase in) inclusion pathology. These studies indicate that compounds that modulate the stress response are a promising approach to treat Parkinson's disease.
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页码:2873 / 2878
页数:6
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