As key molecular chaperone proteins, heat shock proteins (HSPs) represent an important cellular protective mechanism against neuronal cell death in various models of neurological disorders. In this study, we investigated the effect as well as the molecular mechanism of geldanamycin (GA), an inhibitor of Hsp90, on 1-methyl-4-pheny-1,2,3,6-tetrahydropyridine (MPTP)-induced dopaminergic neurotoxicity, a mouse model of Parkinson disease. Neurochemical analysis showed that pretreatment with GA (via intracerebral ventricular injection 24 h prior to MPTP treatment) increased residual dopamine content and tyrosine hydroxylase immunoreactivity in the striatum 24 h after MPTP treatment. To dissect out the molecular mechanism underlying this neuroprotection, we showed that the GA-mediated protection against MPTP was associated with a reduction of cytosolic Hsp90 and an increase in Hsp70, with no significant changes in Hsp40 and Hsp25 levels. Furthermore, in parallel with the induction of Hsp70, striatal nuclear HSF1 levels and HSF1 binding to heat shock element sites in the Hsp70 promoter were significantly enhanced by the GA pretreatment. Together these results suggested that the molecular cascade leading to the induction of Hsp70 is critical to the neuroprotection afforded by GA against MPTP-induced neurotoxicity in the brain and that pharmacological inhibition of Hsp90 may represent a potential therapeutic strategy for Parkinson disease.
PD4 is the second most common human neurodegenerative disorder, affecting 1-3% of people over 65 years old and ϳ10% of those over 80 years old (1-4). The hallmark of PD pathology is the progressive loss of dopaminergic neurons in substantia nigra, leading to profound depletion of dopamine in the striatum, and consequently severe movement abnormalities (1, 3, 4). These pathological changes of PD are associated with formation of Lewy bodies (enriched for ␣-synuclein) in neuritis of dopaminergic and non-dopaminergic neurons (1, 5). For the last three decades, despite the symptomatic relief offered by L-3,4-dihydroxyphenylalanine, no effective neuroprotective strategy for PD has emerged to halt or slow down dopaminergic neurodegeneration (1, 3-6).Heat shock proteins (HSPs) represent an important cellular protective mechanism against a variety of stresses and insults (7-9). HSPs are a large family of evolutionary conserved proteins consisting of subfamilies with molecular masses of ϳ110, 90, 70, 60,40,[15][16][17][18][19][20][21][22][23][24][25][26][27][28][29][30]10,11). Some HSPs (such as Hsp40 and Hsp90) are constitutively expressed, whereas others (such as Hsp70 and Hsp27) are mainly induced after exposure of cells to environmental and physiological stressors (12)(13)(14)(15). A large body of evidence supports a critical role for HSPs in cellular protection against a variety of stressors and insults, including heat, hypoxia, ischemia, excitotoxicity, glucose deprivation, cancer, and aging (13, 16 -24 (32,33). Similarly, overexpression of Hsp70 in dopaminergic neurons using adeno-associa...