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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)
Q6-44
Q39-83
•
Normal ataxin-1
NLS
Expanded ataxin-1
conditional mouse model – enables gene with huge
(Q156) expansion to be switched on and off:
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–
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cerebellar damage is reversible early (to 6 weeks)
partly reversible in mid-course (6-12 weeks)
not reversible in late disease (32 weeks)
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
1
•
•
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Serine 776
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
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?)