Matches in SemOpenAlex for { <https://semopenalex.org/work/W2620212818> ?p ?o ?g. }
- W2620212818 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 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 α-synuclein (or α-synuclein-induced proteotoxic stress) in transfected neuroblastoma cells. HSF1 dysregulation via α-synuclein was 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, the first part of the study strongly suggests that aberrant HSF1 degradation is a key neurodegenerative mechanism underlying α-synucleinopathy. Chronic activation of another cellular stress response, unfolded protein response in ER, has been implicated in tauopathy including Alzheimer’s disease (AD). The unfolded protein response (UPR) in the endoplasmic reticulum (ER) and the cytoplasmic heat stress response are two major stress response systems necessary for maintaining proteostasis for cellular health. Failure of either of these systems, such as in sustained UPR activation or in insufficient heat shock response activation, can lead to the development of neurodegeneration. Alleviation of ER stress and enhancement of heat shock response through heat shock factor 1 (HSF1) activation have previously been considered as attractive potential therapeutic targets for AD—a prevalent and devastating tauopathy. The second part of the study concentrates on our attempts to understand the interplay of the two aforementioned systems and their cooperative role in AD. We provide compelling in vitro and in vivo evidence that strongly suggests an auto-propagating interplay of UPR activation and HSF1 degradation being a common pathogenic feature in both human AD and tau transgenic mouse AD models. We identify aging-associated AD-like neuropathological changes in the hippocampus of HSF1 heterozygous knock-out mice. We speculate that HSF1 loss as an early (earliest) event which constitutes a mechanistic connection between ER stress and tau hyperphosphorylation in tau pathology. Finally, we demonstrate that aged mice lacking HSF1 gene exhibited deficits in hippocampal-dependent functions including short-term working memory, spatial learning and long-term memory. All together, our work supports a previously underappreciated importance of this master stress regulator HSF1 in neuronal functions and in maintaining brain homeostasis." @default.
- W2620212818 created "2017-06-05" @default.
- W2620212818 creator A5037160245 @default.
- W2620212818 date "2022-01-26" @default.
- W2620212818 modified "2023-09-26" @default.
- W2620212818 title "THE ROLE OF HSF1 PROTEIN REGULATION ON NEURODEGENERATION" @default.
- W2620212818 cites W1014881830 @default.
- W2620212818 cites W1528219518 @default.
- W2620212818 cites W1546139069 @default.
- W2620212818 cites W1590357861 @default.
- W2620212818 cites W1604079405 @default.
- W2620212818 cites W1667268002 @default.
- W2620212818 cites W1815844802 @default.
- W2620212818 cites W1881688083 @default.
- W2620212818 cites W1888263661 @default.
- W2620212818 cites W1921865614 @default.
- W2620212818 cites W1964772923 @default.
- W2620212818 cites W1965201584 @default.
- W2620212818 cites W1965709917 @default.
- W2620212818 cites W1966923623 @default.
- W2620212818 cites W1967138582 @default.
- W2620212818 cites W1967464880 @default.
- W2620212818 cites W1968937229 @default.
- W2620212818 cites W1968957266 @default.
- W2620212818 cites W1976452134 @default.
- W2620212818 cites W1977197096 @default.
- W2620212818 cites W1980342220 @default.
- W2620212818 cites W1982265527 @default.
- W2620212818 cites W1983523416 @default.
- W2620212818 cites W1986413832 @default.
- W2620212818 cites W1990009045 @default.
- W2620212818 cites W1991612947 @default.
- W2620212818 cites W1992483894 @default.
- W2620212818 cites W1993069510 @default.
- W2620212818 cites W1995562130 @default.
- W2620212818 cites W1995885857 @default.
- W2620212818 cites W1997604339 @default.
- W2620212818 cites W2004901932 @default.
- W2620212818 cites W2010102311 @default.
- W2620212818 cites W2012405577 @default.
- W2620212818 cites W2013331421 @default.
- W2620212818 cites W2019755584 @default.
- W2620212818 cites W2021180495 @default.
- W2620212818 cites W2021233583 @default.
- W2620212818 cites W2022532556 @default.
- W2620212818 cites W2022547097 @default.
- W2620212818 cites W2024500170 @default.
- W2620212818 cites W2028380145 @default.
- W2620212818 cites W2032920422 @default.
- W2620212818 cites W2034503993 @default.
- W2620212818 cites W2035282018 @default.
- W2620212818 cites W2037262355 @default.
- W2620212818 cites W2037404930 @default.
- W2620212818 cites W2039392338 @default.
- W2620212818 cites W2040124543 @default.
- W2620212818 cites W2040179346 @default.
- W2620212818 cites W2040359453 @default.
- W2620212818 cites W2040454459 @default.
- W2620212818 cites W2043635206 @default.
- W2620212818 cites W2045244036 @default.
- W2620212818 cites W2047159195 @default.
- W2620212818 cites W2048351042 @default.
- W2620212818 cites W2053116497 @default.
- W2620212818 cites W2053514164 @default.
- W2620212818 cites W2055446289 @default.
- W2620212818 cites W2059501379 @default.
- W2620212818 cites W2059524588 @default.
- W2620212818 cites W2064445049 @default.
- W2620212818 cites W2068288454 @default.
- W2620212818 cites W2089791510 @default.
- W2620212818 cites W2091477850 @default.
- W2620212818 cites W2094118946 @default.
- W2620212818 cites W2095963715 @default.
- W2620212818 cites W2098076627 @default.
- W2620212818 cites W2100347985 @default.
- W2620212818 cites W2100978260 @default.
- W2620212818 cites W2102824402 @default.
- W2620212818 cites W2106200048 @default.
- W2620212818 cites W2107339320 @default.
- W2620212818 cites W2107493006 @default.
- W2620212818 cites W2112286580 @default.
- W2620212818 cites W2114746301 @default.
- W2620212818 cites W2120244137 @default.
- W2620212818 cites W2122818115 @default.
- W2620212818 cites W2123714584 @default.
- W2620212818 cites W2123717940 @default.
- W2620212818 cites W2124877751 @default.
- W2620212818 cites W2125985978 @default.
- W2620212818 cites W2127342428 @default.
- W2620212818 cites W2128537698 @default.
- W2620212818 cites W2129091231 @default.
- W2620212818 cites W2130723719 @default.
- W2620212818 cites W2134157741 @default.
- W2620212818 cites W2135309154 @default.
- W2620212818 cites W2141934884 @default.
- W2620212818 cites W2142931463 @default.
- W2620212818 cites W2143595037 @default.
- W2620212818 cites W2144995506 @default.
- W2620212818 cites W2149746962 @default.
- W2620212818 cites W2150656456 @default.