| First Author | Kim E | Year | 2016 |
| Journal | Hum Mol Genet | Volume | 25 |
| Issue | 2 | Pages | 211-22 |
| PubMed ID | 26503960 | Mgi Jnum | J:229169 |
| Mgi Id | MGI:5751003 | Doi | 10.1093/hmg/ddv445 |
| Citation | Kim E, et al. (2016) NEDD4-mediated HSF1 degradation underlies alpha-synucleinopathy. Hum Mol Genet 25(2):211-22 |
| abstractText | 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 alpha-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 stress-protective 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 alpha-synuclein (or alpha-synuclein-induced proteotoxic stress) in transfected neuroblastoma cells. HSF1 dysregulation via alpha-synuclein was confirmed by in vivo assessment of mouse and in situ studies of human specimens with alpha-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 alpha-synuclein toxicity, this study strongly suggests that aberrant HSF1 degradation is a key neurodegenerative mechanism underlying alpha-synucleinopathy. |
