Mechanisms of Suppression of {alpha}-Synuclein Neurotoxicity by Geldanamycin in Drosophila.
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.
Auluck
Pavan K
PK
Department of Neuroscience, University of Pennsylvania, Philadelphia, Pennsylvania 19104, USA.
Meulener
Marc C
MC
Bonini
Nancy M
NM
D000818:Animals; D016227:Benzoquinones; D002470:Cell Survival; D004195:Disease Models, Animal; D004330:Drosophila / Q000378:metabolism*; D004791:Enzyme Inhibitors / Q000494:pharmacology; D018840:HSP70 Heat-Shock Proteins / Q000378:metabolism; D006358:Hot Temperature; D006801:Humans; D015151:Immunoblotting; D007150:Immunohistochemistry; D047029:Lactams, Macrocyclic; D016631:Lewy Bodies / Q000378:metabolism; D009419:Nerve Tissue Proteins / Q000378:metabolism*; D009474:Neurons / Q000378:metabolism; D010300:Parkinson Disease / Q000473:pathology; D011506:Proteins / Q000378:metabolism; D011809:Quinones / Q000494:pharmacology*; D051843:Synucleins; D013696:Temperature; D013997:Time Factors; D051844:alpha-Synuclein
D016227:Benzoquinones; D004791:Enzyme Inhibitors; D018840:HSP70 Heat-Shock Proteins; D047029:Lactams, Macrocyclic; D009419:Nerve Tissue Proteins; D011506:Proteins; D011809:Quinones; C497604:SNCA protein, human; D051843:Synucleins; D051844:alpha-Synuclein; C001277:geldanamycin