title: Posttranslational modification of ataxin-7 at lysine 257 prevents autophagy-mediated turnover of an N-terminal caspase-7 cleavage fragment.
abstract: Polyglutamine (polyQ) expansion within the ataxin-7 protein, a member of the STAGA [SPT3-TAF(II)31-GCN5L acetylase] and TFTC (GCN5 and TRRAP) chromatin remodeling complexes, causes the neurodegenerative disease spinocerebellar ataxia type 7 (SCA7). Proteolytic processing of ataxin-7 by caspase-7 generates N-terminal toxic polyQ-containing fragments that accumulate with disease progression and play an important role in SCA7 pathogenesis. To elucidate the basis for the toxicity of these fragments, we evaluated which posttranslational modifications of the N-terminal fragment of ataxin-7 modulate turnover and toxicity. Here, we show that mutating lysine 257 (K257), an amino acid adjacent to the caspase-7 cleavage site of ataxin-7 regulates turnover of the truncation product in a repeat-dependent manner. Modification of ataxin-7 K257 by acetylation promotes accumulation of the fragment, while unmodified ataxin-7 is degraded. The degradation of the caspase-7 cleavage product is mediated by macroautophagy in cell culture and primary neuron models of SCA7. Consistent with this, the fragment colocalizes with autophagic vesicle markers, and enhanced fragment accumulation increases in these lysosomal structures. We suggest that the levels of fragment accumulation within the cell is a key event in SCA7 neurodegeneration, and enhancing clearance of polyQ-containing fragments may be an effective target to reduce neurotoxicity in SCA7.
authors: Buck Institute for Age Research, Novato, California 94945, USA.
authors: Shona
authors: S
authors: Mookerjee
authors: Theodora
authors: T
authors: Papanikolaou
authors: Stephan J
authors: SJ
authors: Guyenet
authors: Vanitha
authors: V
authors: Sampath
authors: Amy
authors: A
authors: Lin
authors: Cathy
authors: C
authors: Vitelli
authors: Francesco
authors: F
authors: DeGiacomo
authors: Bryce L
authors: BL
authors: Sopher
authors: Sylvia F
authors: SF
authors: Chen
authors: Albert R
authors: AR
authors: La Spada
authors: Lisa M
authors: LM
authors: Ellerby
mesh_terms: D000107:Acetylation; D000818:Animals; D000831:Animals, Newborn; D000067719:Ataxin-7; D001343:Autophagy / Q000235:genetics*; D053179:Caspase 7 / Q000235:genetics / Q000378:metabolism*; D002478:Cells, Cultured; D002531:Cerebellum / Q000166:cytology; D004195:Disease Models, Animal; D006655:Histone Deacetylases / Q000235:genetics / Q000378:metabolism; D006801:Humans; D052119:Lysosomal-Associated Membrane Protein 2 / Q000378:metabolism; D051379:Mice; D008822:Mice, Transgenic; D009088:Mucoproteins / Q000235:genetics*; D009419:Nerve Tissue Proteins / Q000235:genetics / Q000378:metabolism*; D009474:Neurons / Q000502:physiology; D010455:Peptides / Q000235:genetics*; D011328:Prions / Q000235:genetics / Q000378:metabolism; D011499:Protein Processing, Post-Translational / Q000235:genetics*; D021122:Protein Subunits / Q000235:genetics / Q000378:metabolism; D034622:RNA Interference / Q000502:physiology; D020754:Spinocerebellar Ataxias / Q000235:genetics / Q000378:metabolism / Q000473:pathology; D014162:Transfection / Q000379:methods
chemical_list: C000593829:ATXN7 protein, human; D000067719:Ataxin-7; C000593831:Atxn7 protein, mouse; D052119:Lysosomal-Associated Membrane Protein 2; D009088:Mucoproteins; D009419:Nerve Tissue Proteins; D010455:Peptides; D011328:Prions; D021122:Protein Subunits; C010393:lysin, gastropoda; C097188:polyglutamine; D053179:Caspase 7; C543274:Hdac7 protein, mouse; D006655:Histone Deacetylases