RT Journal Article
SR Electronic
T1 Posttranslational Modification of Ataxin-7 at Lysine 257 Prevents Autophagy-Mediated Turnover of an N-Terminal Caspase-7 Cleavage Fragment
JF The Journal of Neuroscience
JO J. Neurosci.
FD Society for Neuroscience
SP 15134
OP 15144
DO 10.1523/JNEUROSCI.4720-09.2009
VO 29
IS 48
A1 Shona Mookerjee
A1 Theodora Papanikolaou
A1 Stephan J. Guyenet
A1 Vanitha Sampath
A1 Amy Lin
A1 Cathy Vitelli
A1 Francesco DeGiacomo
A1 Bryce L. Sopher
A1 Sylvia F. Chen
A1 Albert R. La Spada
A1 Lisa M. Ellerby
YR 2009
UL http://www.jneurosci.org/content/29/48/15134.abstract
AB 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.