Abnormal degradation of the neuronal stress-protective transcription factor HSF1 in Huntington’s disease

Abstract

Huntington's Disease (HD) is a neurodegenerative disease caused by poly-glutamine expansion in the Htt protein, resulting in Htt misfolding and cell death. Expression of the cellular protein folding and pro-survival machinery by heat shock transcription factor 1 (HSF1) ameliorates biochemical and neurobiological defects caused by protein misfolding. We report that HSF1 is degraded in cells and mice expressing mutant Htt, in medium spiny neurons derived from human HD iPSCs and in brain samples from patients with HD. Mutant Htt increases CK2α′ kinase and Fbxw7 E3 ligase levels, phosphorylating HSF1 and promoting its proteasomal degradation. An HD mouse model heterozygous for CK2α′ shows increased HSF1 and chaperone levels, maintenance of striatal excitatory synapses, clearance of Htt aggregates and preserves body mass compared with HD mice homozygous for CK2α′. These results reveal a pathway that could be modulated to prevent neuronal dysfunction and muscle wasting caused by protein misfolding in HD.

WITHDRAWN: Abrogation of heat shock factor 1 (Hsf1) phosphorylation deregulates its activity and lowers activation threshold, leading to obesity in mice

“…al. (17) and another recent study have shown the involvement of Fbxw7 in the degradation of Hsf1 when it is phosphorylated on S303/S307 impacting cancer progression, and aggregation of poly Qcontaining huntingtin protein (18). In one study, it was shown that in melanoma cells expressing lower Fbxw7α levels, Hsf1 is stabilized leading to higher levels of Hsps and more aggressive melanomas and metastasis (17).…”

“…In this model, substitution of serine residues 303 and 307 to glutamic acid or alanine led to repression or derepression, respectively of the Hsf1 activation domain, suggesting that these phosphorylation sites exert intermolecular influence on Hsf1 protein (11). More recent evidence suggest that in addition to transcriptional repression of Hsf1 under normal physiological growth conditions, the phosphorylation of S303/S307 facilitates its binding to Fbxw7α ubiquitin ligase leading to its degradation through the SCF (Skp1-Cul1-Fbox) complex (17,18,35). Both Kourtis, et.…”

“…However, under acute nutrient overload, for example exposure to HFD, the Hsf1 is comparably activated in both WT and Hsf1 303A/307A mice. Finally, Hsf1 S303 and S307 amino acid residues have been suggested to be phosphorylated by GSK3α/β, ERK1/2/MAPK, respectively, as well as by Casein kinase 2α (14)(15)(16)18).…”

“…A recent study suggested that phosphorylation of S303/S307 is required for Fbxw7 ubiquitin ligase binding, ubiquitination and degradation of the Hsf1 (17). In addition, cells expressing poly Q-conjugated huntingtin protein apparently increase the levels of Fbxw7 and Casein kinase 2-dependent Hsf1 phosphorylation on S303/S307 facilitating Hsf1 degradation leading to lower levels of heat shock proteins (Hsps) expression (18).…”

“…The Hsf1 supports the tumor cells to alter the signaling pathways and accommodate alterations in the DNA, protein, and energy metabolism associated with oncogenesis (3-7). As one of the regulators of Hsp expression following stress stimuli, Hsf1 and its downstream targets also play critical role in neurodegenerative diseases (18,22). Hsf1 also plays a role in maintaining redox homeostasis in the heart and kidney, female fertility, olfactory neurogenesis and development (9).…”