Details

Autor(en) / Beteiligte

• Chatterjee, Megha
• Steffan, Joan S.
• Lukacsovich, Tamas
• Marsh, J. Lawrence
• Agrawal, Namita

Titel

Serine residues 13 and 16 are key modulators of mutant huntingtin induced toxicity in Drosophila

Ist Teil von

• Experimental neurology, 2021-04, Vol.338, p.113463, Article 113463

Ort / Verlag

United States: Elsevier Inc

Erscheinungsjahr

2021

Quelle

Alma/SFX Local Collection

Beschreibungen/Notizen

• Poly-glutamine expansion near the N-terminus of the huntingtin protein (HTT) is the prime determinant of Huntington's disease (HD) pathology; however, post-translational modifications and protein context are also reported to influence poly-glutamine induced HD toxicity. The impact of phosphorylating serine 13/16 of mutant HTT (mHTT) on HD has been documented in cell culture and murine models. However, endogenous processing of the human protein in mammalian systems complicates the interpretations. Therefore, to study the impact of S13/16 phosphorylation on the subcellular behavior of HTT under a controlled genetic background with minimal proteolytic processing of the human protein, we employed Drosophila as the model system. We ectopically expressed full-length (FL) and exon1 fragment of human HTT with phosphomimetic and resistant mutations at serines 13 and 16 in different neuronal populations. Phosphomimetic mHTT aggravates and the phosphoresistant mutation ameliorates mHTT-induced toxicity in the context of both FL- and exon1- mHTT in Drosophila although in all cases FL appears less toxic than exon1. Our observations strongly indicate that the phosphorylation status of S13/16 can affect HD pathology in Drosophila and these residues can be potential targets for affecting HD pathogenesis. •HTT behavior is studied in fly model which provides a controlled genetic background.•S13/16A phosphoresistant mutation increases lifespan of Drosophila expressing full-length and exon1 mHTT.•S13/16A reduces motor dysfunction caused by full-length and exon1 mHTT in Drosophila adults.•S13/16A ameliorates exon1 and full-length mHTT mediated cytotoxicity in Drosophila.•Expanded polyQ in the context of full-length HTT does not cause aggregates to form in vivo.