Loss of Hsp110 Leads to Age-Dependent Tau Hyperphosphorylation and Early Accumulation of Insoluble Amyloid β

Abstract

Accumulation of tau into neurofibrillary tangles is a pathological consequence of Alzheimer's disease and other tauopathies. Failures of the quality control mechanisms by the heat shock proteins (Hsps) positively correlate with the appearance of such neurodegenerative diseases. However, in vivo genetic evidence for the roles of Hsps in neurodegeneration remains elusive. Hsp110 is a nucleotide exchange factor for Hsp70, and direct substrate binding to Hsp110 may facilitate substrate folding. Hsp70 complexes have been implicated in tau phosphorylation state and amyloid precursor protein (APP) processing. To provide evidence for a role for Hsp110 in central nervous system homeostasis, we have generated hsp110 ؊/؊ mice. Our results show that hsp110 ؊/؊ mice exhibit accumulation of hyperphosphorylated-tau (p-tau) and neurodegeneration. We also demonstrate that Hsp110 is in complexes with tau, other molecular chaperones, and protein phosphatase 2A (PP2A). Surprisingly, high levels of PP2A remain bound to tau but with significantly reduced activity in brain extracts from aged hsp110 ؊/؊ mice compared to brain extracts from wild-type mice. Mice deficient in the Hsp110 partner (Hsp70) also exhibit a phenotype comparable to that of hsp110 ؊/؊ mice, confirming a critical role for Hsp110-Hsp70 in maintaining tau in its unphosphorylated form during aging. In addition, crossing hsp110 ؊/؊ mice with mice overexpressing mutant APP (APP␤sw) leads to selective appearance of insoluble amyloid ␤42 (A␤42), suggesting an essential role for Hsp110 in APP processing and A␤ generation. Thus, our findings provide in vivo evidence that Hsp110 plays a critical function in tau phosphorylation state through maintenance of efficient PP2A activity, confirming its role in pathogenesis of Alzheimer's disease and other tauopathies.

Structure and function of Hip, an attenuator of the Hsp70 chaperone cycle

“…In line with this finding, deletion of Hsp105 causes accumulation of hyper-phosphorylated tau and neurofibrillary tangles in mice (Eroglu et al, 2010). Taken together, the multiple functions of NEFs indicate the functional significance of NEFs in the Hsp70 molecular machinery.…”

“…Furthermore, Hsp110s were found associated with amyloidogenic proteins and disease-related protein aggregates such as from mutant superoxide dismutase 1 (SOD1) or tau (Eroglu et al, 2010;Olzscha et al, 2011;Yamashita et al, 2007). More recently, Hsp110 has been implicated to empower Hsp70-Hsp40 to efficiently resolubilize and reactivate substrate protein in vitro (Rampelt et al, 2012 Hsp110 is an essential component of protein disaggregation machinery (Rampelt et al, 2012).…”

Hyperthermia Stress Activates Heat Shock Protein Expression via Propyl Isomerase 1 Regulation with Heat Shock Factor 1

“…To our surprise, HSP gene expression was attenuated in PIN1-deficient neurons after heat shock treatment, indicating that PIN1 is indispensable for heat shock-induced HSP gene expression. Moreover, both HSP110/105 and PIN1 deficiency have been shown to result in age-dependent tau hyperphosphorylation and the early accumulation of insoluble amyloid proteins (28,35,38). The accumulation of hyperphosphorylated tau and insoluble amyloid proteins is a pathological consequence of Alzheimer's disease.…”

Hierarchical Functional Specificity of Cytosolic Heat Shock Protein 70 (Hsp70) Nucleotide Exchange Factors in Yeast

“…Marinesco-Sjøgren syndrome is an autosomal recessive cerebellar ataxia caused by a mutation in Sil1 (BAP), an NEF for the ERresident Hsp70 BiP (45). Loss of Hsp110 is additionally associated with Tau pathology in a mouse model and huntingtinrelated neurodegeneration in a Drosophila model (46,47).…”