Editing HSF1

[[Key concepts in ALS]]

[https://en.wikipedia.org/wiki/HSF1 Wikipedia]: ''The HSF1 protein regulates the heat shock response (HSR) pathway in humans by acting as the major transcription factor for heat shock proteins. The HSR plays a protective role by ensuring proper folding and distribution of proteins within cells. This pathway is induced by not only temperature stress, but also by a variety of other stressors such as hypoxic conditions and exposure to contaminants.[6] HSF1 transactivates genes for many cytoprotective proteins involved in heat shock, DNA damage repair, and metabolism. This illustrates the versatile role of HSF1 in not only the heat shock response, but also in aging and diseases.[6]''

== Effects on ALS ==

''Protein homeostatic regulators have been shown to ameliorate single, loss-of-function protein diseases but not to treat broader animal disease models that may involve cell death. Diseases often trigger protein homeostatic instability that disrupts the delicate balance of normal cellular viability. Furthermore, protein homeostatic regulators have been delivered invasively and not with simple oral administration. '''Here, we report the potent homeostatic abilities of celastrol to promote cell survival, decrease inflammation, and maintain cellular homeostasis in three different disease models of apoptosis and inflammation involving hepatocytes and cardiomyocytes.''' We show that celastrol significantly recovers the left ventricular function and myocardial remodeling following models of acute myocardial infarction and doxorubicin-induced cardiomyopathy by diminishing infarct size, apoptosis, and inflammation. Celastrol prevents acute liver dysfunction and promotes hepatocyte survival after toxic doses of thioacetamide. '''Finally, we show that heat shock response (HSR) is necessary and sufficient for the recovery abilities of celastrol.''' Our observations may have dramatic clinical implications to ameliorate entire disease processes even after cellular injury initiation by using an orally delivered HSR activator.'' {{#pmid:25300203|sharma2015}}

''Heat shock proteins (Hsps) are ubiquitously expressed chaperone proteins that enable cells to cope with environmental stresses that cause misfolding and denaturation of proteins. With aging this protein quality control machinery becomes less effective, reducing the ability of cells to cope with damaging environmental stresses and disease-causing mutations. In neurodegenerative disorders such as Amyotrophic Lateral Sclerosis (ALS), such mutations are known to result in protein misfolding, which in turn results in the formation of intracellular aggregates cellular dysfunction and eventual neuronal death. The exact cellular pathology of ALS and other neurodegenerative diseases has been elusive and thus, hindering the development of effective therapies. However, a common scheme has emerged across these "protein misfolding" disorders, in that the mechanism of disease involves one or more aspects of proteostasis; from DNA transcription, RNA translation, to protein folding, transport and degradation via proteosomal and autophagic pathways. Interestingly, members of the Hsp family are involved in each of these steps facilitating normal protein folding, regulating the rate of protein synthesis and degradation. In this short review we summarize the evidence that suggests that ALS is a disease of protein dyshomeostasis in which Hsps may play a key role. Overwhelming evidence now indicates that enabling protein homeostasis to cope with disease-causing mutations might be a successful therapeutic strategy in ALS, as well as other neurodegenerative diseases. Novel small molecule co-inducers of Hsps appear to be able to achieve this aim. Arimoclomol, a hydroxylamine derivative, has shown promising results in cellular and animal models of ALS, as well as other protein misfolding diseases such as Inclusion Body Myositis (IBM). Initial clinical investigations of Arimoclomol have shown promising results. Therefore, it is possible that the long series of unsuccessful clinical trials for ALS may soon be reversed, as optimal targeting of proteostasis in ALS may now be possible, and may deliver clinical benefit to patients.'' {{#pmid:28943839|kalmar2017}}

''TDP-43 pathology marks a spectrum of multisystem proteinopathies including amyotrophic lateral sclerosis, frontotemporal lobar degeneration, and sporadic inclusion body myositis. Surprisingly, it has been challenging to recapitulate this pathology, highlighting an incomplete understanding of TDP-43 regulatory mechanisms. Here we provide evidence supporting TDP-43 acetylation as a trigger for disease pathology. Using cultured cells and mouse skeletal muscle, we show that TDP-43 acetylation-mimics promote TDP-43 phosphorylation and ubiquitination, perturb mitochondria, and initiate degenerative inflammatory responses that resemble sporadic inclusion body myositis pathology. Analysis of functionally linked amyotrophic lateral sclerosis proteins revealed recruitment of p62, ubiquilin-2, and optineurin to TDP-43 aggregates. We demonstrate that TDP-43 acetylation-mimic pathology is potently suppressed by an HSF1-dependent mechanism that disaggregates TDP-43. Our study illustrates bidirectional TDP-43 processing in which TDP-43 aggregation is targeted by a coordinated chaperone response. Thus, activation or restoration of refolding mechanisms may alleviate TDP-43 aggregation in tissues that are uniquely susceptible to TDP-43 proteinopathies.TDP-43 aggregation is linked to various diseases including amyotrophic lateral sclerosis. '''Here the authors show that acetylation of the protein triggers TDP-43 pathology in cultured cells and mouse skeletal muscle, which can be cleared through an HSF1-dependent chaperone mechanism that disaggregates the protein.''''' {{#pmid:28724966|wang2017}}

== References ==

[[Category:Key concepts]]
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	[https://en.wikipedia.org/wiki/HSF1 Wikipedia]: ''The HSF1 protein regulates the heat shock response (HSR) pathway in humans by acting as the major transcription factor for heat shock proteins. The HSR plays a protective role by ensuring proper folding and distribution of proteins within cells. This pathway is induced by not only temperature stress, but also by a variety of other stressors such as hypoxic conditions and exposure to contaminants.[6] HSF1 transactivates genes for many cytoprotective proteins involved in heat shock, DNA damage repair, and metabolism. This illustrates the versatile role of HSF1 in not only the heat shock response, but also in aging and diseases.[6]''		[https://en.wikipedia.org/wiki/HSF1 Wikipedia]: ''The HSF1 protein regulates the heat shock response (HSR) pathway in humans by acting as the major transcription factor for heat shock proteins. The HSR plays a protective role by ensuring proper folding and distribution of proteins within cells. This pathway is induced by not only temperature stress, but also by a variety of other stressors such as hypoxic conditions and exposure to contaminants.[6] HSF1 transactivates genes for many cytoprotective proteins involved in heat shock, DNA damage repair, and metabolism. This illustrates the versatile role of HSF1 in not only the heat shock response, but also in aging and diseases.[6]''
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	== Effects on ALS ==		== Effects on ALS ==