Molecular Studies of Spinocerebellar Ataxia Type 1
Spinocerebellar ataxia type 1 (SCA1) is an autosomal dominant neurodegenerative disease caused by expansion of a polyglutamine (CAG) tract in the protein ataxin-1 (Atx-1). We have shown that this expanded CAG tract alters the protein's conformation and causes it to gain some toxic function; the misfolded protein resists degradation and eventually accumulates into nuclear inclusions in neurons. Long before accumulation or even clinical symptoms are apparent, however, the mutant protein alters gene expression in neurons. In mice, these gene expression changes begin within a week of birth. Ataxin-1 null mice have a learning deficit, they do not develop any features of SCA1; mice overexpressing wild-type ataxin-1 or expressing ataxin-1 with a greatly expanded CAG repeat tract develop the characteristic signs of SCA1. In seeking to understand the normal function of this protein, we have found that both wild-type and mutant ataxin-1 share interacting proteins and genetic modifiers: both forms are phosphorylated by Akt at S776, and ataxin-1 induced degeneration can be prevented or suppressed by either eliminating this phosphorylation site or decreasing Akt activity. When we learned that the repressor Gfi-1 is a physical and genetic interactor of ataxin-1, and that Gfi-1 null mice develop Purkinje cell degeneration, we reasoned that a component of the toxic gain-of-function mechanism in SCA1 might actually be enhancement of ataxin-1's normal functions or interactions with its usual partners.
We have recently shown that, indeed, the altered conformation of ataxin-1 increases its tendency to form complexes with some of its normal interactors and reduces its ability to complex with others, leading to a complicated gain and loss of function of normal ataxin-1 activity. We are currently investigating the effects of the disease modifiers in mammalian cells and in our SCA1 mouse model to identify targets that could alter disease course. We are also studying interactomes that trace networks of proteins that interact with ataxin-1 and other proteins involved in the other inherited ataxias, to better characterize the proteins and understand the peculiar vulnerability of Purkinje cells to this class of diseases. Successful interventional trials in the SCA1 mice using drugs that have been shown to modify the disease course have led us to begin clinical trials in collaboration with the NIH Clinical Research Center .
Relevance of the project to IDDRC mission:
SCA1 and other polyglutamine diseases cause significant disability and neurologic impairments. Understanding the disease mechanism in SCA1 through cross-species studies and carrying out pre-clinical studies in mouse models will have far-reaching implications not only for this class of diseases but also for translational research initiatives in neurodegeneration.