Geldanamycin Induces Heat Shock Protein 70 and Protects against MPTP-induced Dopaminergic Neurotoxicity in Mice

Abstract

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...

Collaboration of geldanamycin-activated P70S6K and Hsp70 against beta-amyloid-induced hippocampal apoptosis: an approach to long-term memory and learning

“…Several experiments using administration of GA in vitro have indicated its neuroprotective activity via preventing α-synuclein aggregation and neurotoxicity and protecting dopaminergic neuron death (McLean et al 2004;Shen et al 2005). In the terms of AD studies, GA has been shown to promote the binding of tau protein to microtubules, leading to a significant reduction in tau aggregation (Dou et al 2003), although its action on Aβ-mediated apoptosis and oxidative stress has not been yet studied.…”

Synergism between Arsenic Trioxide and Heat Shock Protein 90 Inhibitors on Signal Transducer and Activator of Transcription Protein 3 Activity—Pharmacodynamic Drug-Drug Interaction Modeling

“…Heat shock protein (HSP) 90 is implicated in maintaining the conformation, stability, and function of key proteins involved in signal transduction pathways (3), and we therefore hypothesized that HSP90 inhibitors [geldanamycin, 17-allylamino-17-demethoxygeldanamycin (17-AAG), and 17-(dimethylaminoethylamino)-17-demethoxygeldanamycin (NSC 707545, 17-DMAG)] would potentiate the effect of ATO on constitutive STAT3 activity in AML cells. One concern was that up-regulation of HSP70, a protein known to inhibit apoptosis (4,5), by exposure to either ATO (6 -8) or HSP90 inhibitors (9,10), might abrogate their effect on constitutive STAT3 activity and survival.…”

MPTP-induced model of Parkinson's disease in heat shock protein 70.1 knockout mice

“…Genetic studies in Drosophila showed that the overexpression of Hsp70 suppressed polyglutamine-induced neurodegeneration in vivo (22). Shen et al reported that the induction of Hsp70 is critical to the neuroprotection afforded by geldanamycin against MPTP-induced neurotoxicity in the mouse brain (23). Moreover, induction of Hsp70 by prior exposure to heat shock protects against MPP + -induced neuronal cell death in cultured PC12 cells (11) and against α-synuclein aggregation in human H4 neuroglioma cells (7,8).…”