American Academy of Neurology Chicago – April 2008 Frontiers in Clinical Neuroscience Plenary Session Protein interactions and cell signalling pathways.

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American Academy of Neurology Chicago – April 2008 Frontiers in Clinical Neuroscience Plenary Session Protein interactions and cell signalling pathways in SCA 1 pathogenesis – targets for therapeutics Harry T. Orr University of Minnesota

SCA 1 involves expansion of (CAG)n triplet repeat at starting end of ataxin 1 gene, leading to longer than normal string of glutamines (Q’s) conditional mouse model – enables gene with huge (Q156) expansion to be switched on and off: cerebellar damage is reversible early (to 6 weeks) partly reversible in mid-course (6-12 weeks) not reversible in late disease (32 weeks) Q6-44 Normal ataxin-1 Q39-83 NLS Expanded ataxin-1

Ataxin 1 ( full-length Q30); anti-ataxin 1 N-terminal

Ataxin 1 ( full-length Q85/FLAG); anti-ataxin 1 N-terminal

Ataxin 1 (truncated Q85/FLAG); anti-ataxin 1 N-terminal

SCA 1 expanded ataxin-1  aggregates, but toxicity is due to soluble expanded ataxin-1 not its aggregates absence of expanded ataxin-1 early in development (P7-14 in mouse) makes cerebellum less susceptible to damage by expanded ataxin-1 in later (mouse) life – due to decreased disruption of another gene (ROR) important for normal development of cerebellum

What causes toxicity in SCA 1? – 1) * – Qn serine at position 776 can be phosphorylated (joined to a phosphate group to change its size and electrical charge) this is made much more likely by an expanded Qn at the other end of the protein (as occurs in SCA 1) mutating the serine to another amino-acid (alanine) that cannot be phosphorylated prevents toxicity from expanded ataxin-1 1 Serine 776

What causes toxicity in SCA 1? – 2) mutating the serine to yet another amino acid (glutamic acid) mimics the size and charge effect of phosphorylating the serine, and causes normal ataxin-1 to become toxic Therefore, if we could prevent or reverse serine 776 phosphorylation, we could prevent or reverse early disease (specific kinase inhibitor/phosphatase activator?)