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 journalArticle

18 Citations (Scopus)

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

Fingerprint

Synucleins
Proteasome Endopeptidase Complex
Ubiquitin
heat shock transcription factor
Apoptosis Regulatory Proteins
Proteins
Molecular Chaperones
Ubiquitin-Protein Ligases
Protein Stability
Poisons
Acetylation
Heat-Shock Proteins
Neuroblastoma
Homeostasis
Transcription Factors
Neurons
DNA
Therapeutics

All Science Journal Classification (ASJC) codes

  • Molecular Biology
  • Genetics
  • Genetics(clinical)

Cite this

Kim, E., Wang, B., Sastry, N., Masliah, E., Nelson, P. T., Cai, H., & Liao, F-F. (2016). NEDD4-mediated HSF1 degradation underlies α-synucleinopathy. Human Molecular Genetics, 25(2), 211-222. https://doi.org/10.1093/hmg/ddv445

NEDD4-mediated HSF1 degradation underlies α-synucleinopathy. / Kim, Eunhee; Wang, Bin; Sastry, Namratha; Masliah, Eliezer; Nelson, Peter T.; Cai, Huaibin; Liao, Francesca-Fang.

In: Human Molecular Genetics, Vol. 25, No. 2, 15.01.2016, p. 211-222.

Research output: Contribution to journalArticle

Kim, E, Wang, B, Sastry, N, Masliah, E, Nelson, PT, Cai, H & Liao, F-F 2016, 'NEDD4-mediated HSF1 degradation underlies α-synucleinopathy', Human Molecular Genetics, vol. 25, no. 2, pp. 211-222. https://doi.org/10.1093/hmg/ddv445
Kim E, Wang B, Sastry N, Masliah E, Nelson PT, Cai H et al. NEDD4-mediated HSF1 degradation underlies α-synucleinopathy. Human Molecular Genetics. 2016 Jan 15;25(2):211-222. https://doi.org/10.1093/hmg/ddv445
Kim, Eunhee ; Wang, Bin ; Sastry, Namratha ; Masliah, Eliezer ; Nelson, Peter T. ; Cai, Huaibin ; Liao, Francesca-Fang. / NEDD4-mediated HSF1 degradation underlies α-synucleinopathy. In: Human Molecular Genetics. 2016 ; Vol. 25, No. 2. pp. 211-222.
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