NEDD4-mediated HSF1 degradation underlies α-synucleinopathy

Eunhee Kim, Bin Wang, Namratha Sastry, Eliezer Masliah, Peter T. Nelson, Huaibin Cai, Francesca Fang Liao

Research output: Contribution to journalArticlepeer-review

64 Scopus citations

Abstract

Cellular protein homeostasis is achieved by a delicate network of molecular chaperones and various proteolytic processes such as ubiquitin-proteasome system (UPS) to avoid a build-up of misfolded protein aggregates. The latter is a common denominator of neurodegeneration. Neurons are found to be particularly vulnerable to toxic stress from aggregation-prone proteins such as α-synuclein. Induction of heat-shock proteins (HSPs), such as through activated heat shock transcription factor 1 (HSF1) via Hsp90 inhibition, is being investigated as a therapeutic option for proteinopathic diseases. HSF1 is a master stressprotective transcription factor which activates genes encoding protein chaperones (e.g. iHsp70) and anti-apoptotic proteins. However, whether and how HSF1 is dysregulated during neurodegeneration has not been studied. Here, we discover aberrant HSF1 degradation by aggregated α-synuclein (or α-synuclein-induced proteotoxic stress) in transfected neuroblastoma cells. HSF1 dysregulation via α-synucleinwas confirmed by in vivo assessment of mouse and in situ studies of human specimens with α-synucleinopathy. We demonstrate that elevated NEDD4 is implicated as the responsible ubiquitin E3 ligase for HSF1 degradation through UPS. Furthermore, pharmacologically induced SIRT1-mediated deacetylation can attenuate aberrant NEDD4-mediated HSF1 degradation. Indeed, we define the acetylation status of the Lys 80 residue located in the DNA-binding domain of HSF1 as a critical factor in modulating HSF1 protein stability in addition to its previously identified role in the transcriptional activity. Together with the finding that preserving HSF1 can alleviate α-synuclein toxicity, this study strongly suggests that aberrant HSF1 degradation is a key neurodegenerative mechanism underlying α-synucleinopathy.

Original languageEnglish
Pages (from-to)211-222
Number of pages12
JournalHuman Molecular Genetics
Volume25
Issue number2
DOIs
StatePublished - Jan 15 2016

Bibliographical note

Publisher Copyright:
© The Author 2015. Published by Oxford University Press.

ASJC Scopus subject areas

  • Molecular Biology
  • Genetics
  • Genetics(clinical)

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