A primary pathologic component of Alzheimer's disease (AD) is the formation of neurofibrillary tangles composed of hyperphosphorylated tau (p-tau). Expediting the removal of these p-tau species may be a relevant therapeutic strategy. Here we report that inhibition of Hsp90 led to decreases in p-tau levels independent of heat shock factor 1 (HSF1) activation. A critical mediator of this mechanism was carboxy terminus of Hsp70-interacting protein (CHIP), a tau ubiquitin ligase. Cochaperones were also involved in Hsp90-mediated removal of p-tau, while those of the mature Hsp90 refolding complex prevented this effect. This is the first demonstration to our knowledge that blockade of the refolding pathway promotes p-tau turnover through degradation. We also show that peripheral administration of a novel Hsp90 inhibitor promoted selective decreases in p-tau species in a mouse model of tauopathy, further suggesting a central role for the Hsp90 complex in the pathogenesis of tauopathies. When taken in the context of known high-affinity Hsp90 complexes in affected regions of the AD brain, these data implicate a central role for Hsp90 in the development of AD and other tauopathies and may provide a rationale for the development of novel Hsp90-based therapeutic strategies.

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Mutation in leucine-rich repeat kinase-2 (LRRK2) is the most common cause of late-onset Parkinson's disease (PD). Although most cases of PD are sporadic, some are inherited, including those caused by LRRK2 mutations. Because these mutations may be associated with a toxic gain of function, controlling the expression of LRRK2 may decrease its cytotoxicity. Here we show that the carboxyl terminus of HSP70-interacting protein (CHIP) binds, ubiquitinates, and promotes the ubiquitin proteasomal degradation of LRRK2. Overexpression of CHIP protects against and knockdown of CHIP exacerbates toxicity mediated by mutant LRRK2. Moreover, HSP90 forms a complex with LRRK2, and inhibition of HSP90 chaperone activity by 17AAG leads to proteasomal degradation of LRRK2, resulting in increased cell viability. Thus, increasing CHIP E3 ligase activity and blocking HSP90 chaperone activity can prevent the deleterious effects of LRRK2. These findings point to potential treatment options for LRRK2-associated PD.is a progressive neurodegenerative disorder pathologically characterized by loss of dopaminergic neurons from the substantia nigra and the presence of Lewy bodies (1-3). The etiology of PD is incompletely understood but appears to involve both genetic and environmental factors. To date, 5 genes (␣-synuclein, parkin, DJ-1, PINK-1, and LRRK2) are associated with genetic forms of PD that closely resemble idiopathic PD (4-10). Mutation in LRRK2 is the most frequent genetic cause of PD (11). Patients with LRRK2 mutations exhibit clinical and neurochemical phenotypes that are indistinguishable from sporadic PD (9, 10). These patients suffer neuronal loss and gliosis in the substantia nigra and development of Lewy bodies, and also exhibit pleomorphic neuropathology, including ␣-synuclein and tau pathology (9, 12, 13). Thus, LRRK2 is important for the pathogenesis of several major neurodegenerative disorders associated with parkinsonism.LRRK2, a member of the ROCO protein family, contains a guanosine triphosphatase (GTPase), a C-terminal of Ras domain with a kinase effector domain (14), repeat sequences beginning at the N terminus, and a leucine-rich repeat structure near its GTPase domain (15). LRRK2 is localized to membranous structures, where it may be in involved in neuronal polarity (16)(17)(18). Mutations in LRRK2 are frequent in autosomaldominant PD as well as sporadic PD (19-23). PD-associated LRRK2 mutants seem to enhance kinase activity, and mutant LRRK2-mediated neuronal toxicity requires GTP-binding and kinase activity (17,(24)(25)(26).The ubiquitin proteosomal system (UPS) appears to regulate LRRK2 level, with little influence from the autophagic and lysosomal degradation pathways (17). LRRK2 also dimerizes and interacts with HSP90 (18, 27, 28), which is somehow involved in controlling LRRK2 levels. The identity of the E3 ligase and the mechanisms that regulate the stability of LRRK2 via HSP90 are not known. Whether the levels of LRRK2 are linked to toxicity also is unclear.The carboxyl terminus of HSP70-interacting protei...