title: Proteolytic cleavage of ataxin-7 by caspase-7 modulates cellular toxicity and transcriptional dysregulation.
abstract: Spinocerebellar ataxia type 7 (SCA7) is a polyglutamine (polyQ) disorder characterized by specific degeneration of cerebellar, brainstem, and retinal neurons. Although they share little sequence homology, proteins implicated in polyQ disorders have common properties beyond their characteristic polyQ tract. These include the production of proteolytic fragments, nuclear accumulation, and processing by caspases. Here we report that ataxin-7 is cleaved by caspase-7, and we map two putative caspase-7 cleavage sites to Asp residues at positions 266 and 344 of the ataxin-7 protein. Site-directed mutagenesis of these two caspase-7 cleavage sites in the polyQ-expanded form of ataxin-7 produces an ataxin-7 D266N/D344N protein that is resistant to caspase cleavage. Although ataxin-7 displays toxicity, forms nuclear aggregates, and represses transcription in human embryonic kidney 293T cells in a polyQ length-dependent manner, expression of the non-cleavable D266N/D344N form of polyQ-expanded ataxin-7 attenuated cell death, aggregate formation, and transcriptional interference. Expression of the caspase-7 truncation product of ataxin-7-69Q or -92Q, which removes the putative nuclear export signal and nuclear localization signals of ataxin-7, showed increased cellular toxicity. We also detected N-terminal polyQ-expanded ataxin-7 cleavage products in SCA7 transgenic mice similar in size to those generated by caspase-7 cleavage. In a SCA7 transgenic mouse model, recruitment of caspase-7 into the nucleus by polyQ-expanded ataxin-7 correlated with its activation. Our results, thus, suggest that proteolytic processing of ataxin-7 by caspase-7 may contribute to SCA7 disease pathogenesis.
authors.affiliation: Buck Institute for Age Research, Novato, California, 94945, USA.
authors.forename: Jessica E
authors.initials: JE
authors.lastname: Young
authors.forename: Launce
authors.initials: L
authors.lastname: Gouw
authors.forename: Stephanie
authors.initials: S
authors.lastname: Propp
authors.forename: Bryce L
authors.initials: BL
authors.lastname: Sopher
authors.forename: Jillian
authors.initials: J
authors.lastname: Taylor
authors.forename: Amy
authors.initials: A
authors.lastname: Lin
authors.forename: Evan
authors.initials: E
authors.lastname: Hermel
authors.forename: Anna
authors.initials: A
authors.lastname: Logvinova
authors.forename: Sylvia F
authors.initials: SF
authors.lastname: Chen
authors.forename: Shiming
authors.initials: S
authors.lastname: Chen
authors.forename: Dale E
authors.initials: DE
authors.lastname: Bredesen
authors.forename: Ray
authors.initials: R
authors.lastname: Truant
authors.forename: Louis J
authors.initials: LJ
authors.lastname: Ptacek
authors.forename: Albert R
authors.initials: AR
authors.lastname: La Spada
authors.forename: Lisa M
authors.initials: LM
authors.lastname: Ellerby
mesh_terms: D000818:Animals; D000067719:Ataxin-7; D019556:COS Cells; D053179:Caspase 7 / Q000378:metabolism*; D002460:Cell Line; D002531:Cerebellum / Q000378:metabolism; D002522:Chlorocebus aethiops; D005786:Gene Expression Regulation; D006801:Humans; D051379:Mice; D008822:Mice, Transgenic; D016297:Mutagenesis, Site-Directed; D009154:Mutation; D009419:Nerve Tissue Proteins / Q000737:chemistry / Q000235:genetics* / Q000502:physiology; D010455:Peptides / Q000378:metabolism; D014158:Transcription, Genetic
chemical_list: C000593829:ATXN7 protein, human; D000067719:Ataxin-7; C000593831:Atxn7 protein, mouse; D009419:Nerve Tissue Proteins; D010455:Peptides; C097188:polyglutamine; D053179:Caspase 7