Abstract：
:The N-terminal 17 amino acids of huntingtin (NT17) can be phosphorylated on serines 13 and 16; however, the significance of these modifications in Huntington's disease pathogenesis remains unknown. In this study, we developed BAC transgenic mice expressing full-length mutant huntingtin (fl-mhtt) with serines 13 and 16 mutated to either aspartate (phosphomimetic or SD) or alanine (phosphoresistant or SA). Both mutant proteins preserve the essential function of huntingtin in rescuing knockout mouse phenotypes. However, fl-mhtt-induced disease pathogenesis, including motor and psychiatric-like behavioral deficits, mhtt aggregation, and selective neurodegeneration are abolished in SD but preserved in SA mice. Moreover, modification of these serines in expanded repeat huntingtin peptides modulates aggregation and amyloid fibril formation in vitro. Together, our findings demonstrate that serines 13 and 16 are critical determinants of fl-mhtt-induced disease pathogenesis in vivo, supporting the targeting of huntingtin NT17 domain and its modifications in HD therapy.
journal_name
Neuronjournal_title
Neuronauthors
Gu X,Greiner ER,Mishra R,Kodali R,Osmand A,Finkbeiner S,Steffan JS,Thompson LM,Wetzel R,Yang XWdoi
10.1016/j.neuron.2009.11.020subject
Has Abstractpub_date
2009-12-24 00:00:00pages
828-40issue
6eissn
0896-6273issn
1097-4199pii
S0896-6273(09)00936-2journal_volume
64pub_type
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