“I worked with Maria Cho as a colleague at WuXi AppTec and at the time, I was new to both the CRO environment and the biotechnology field. Maria was extremely helpful to me and was happy to teach me everything I needed to know to do the biotechnology part of my job Although it was not part of her specific job description, Maria volunteered to help train the new salespeople. She was very generous with her time and spent hours reviewing training presentations with the account managers. The training she did was excellent because of her ability to make the complex understandable and to distill an overload of information down to exactly what was needed. Maria was a valuable resource to the salesforce both technically and with her timely and valuable business insight. It was a pleasure working with Maria and learning from her.”
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Are you in Chicago next week for the Institute of Food Technologists (IFT) annual event and expo? If so come meet Jonathan Hanley our Head of Food &…
Are you in Chicago next week for the Institute of Food Technologists (IFT) annual event and expo? If so come meet Jonathan Hanley our Head of Food &…
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🔗 A new report released by Boston Consulting Group (BCG), GFI, and Synthesis Capital reveals striking parallels between the alternative protein and…
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I'm excited to be launching this new report today, alongside Boston Consulting Group (BCG) and The Good Food Institute. Alternative proteins have…
I'm excited to be launching this new report today, alongside Boston Consulting Group (BCG) and The Good Food Institute. Alternative proteins have…
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Cytoplasmic retention of polyglutamine-expanded androgen receptor ameliorates disease via autophagy in a mouse model of spinal and bulbar muscular atrophy
Human molecular genetics
The nucleus is the primary site of protein aggregation in many polyglutamine diseases, suggesting a central role in pathogenesis. In SBMA, the nucleus is further implicated by the critical role for disease of androgens, which promote the nuclear translocation of the mutant androgen receptor (AR). To clarify the importance of the nucleus in SBMA, we genetically manipulated the nuclear localization signal of the polyglutamine-expanded AR. Transgenic mice expressing this mutant AR displayed…
The nucleus is the primary site of protein aggregation in many polyglutamine diseases, suggesting a central role in pathogenesis. In SBMA, the nucleus is further implicated by the critical role for disease of androgens, which promote the nuclear translocation of the mutant androgen receptor (AR). To clarify the importance of the nucleus in SBMA, we genetically manipulated the nuclear localization signal of the polyglutamine-expanded AR. Transgenic mice expressing this mutant AR displayed inefficient nuclear translocation and substantially improved motor function compared with SBMA mice. While we found that nuclear localization of polyglutamine-expanded AR is required for SBMA, we also discovered, using cell models of SBMA, that it is insufficient for both aggregation and toxicity and requires androgens for these disease features. Through our studies of cultured motor neurons, we further found that the autophagic pathway was able to degrade cytoplasmically retained expanded AR and represents an endogenous neuroprotective mechanism. Moreover, pharmacologic induction of autophagy rescued motor neurons from the toxic effects of even nuclear-residing mutant AR, suggesting a therapeutic role for autophagy in this nucleus-centric disease. Thus, our studies firmly establish that polyglutamine-expanded AR must reside within nuclei in the presence of its ligand to cause SBMA. They also highlight a mechanistic basis for the requirement for nuclear localization in SBMA neurotoxicity, namely the lack of mutant AR removal by the autophagic protein degradation pathway.
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