The inherited ataxias comprise a group of genetically distinct diseases with an overall prevalence of approximately 10/100,000. Spinocerebellar ataxia type 2 (SCA2) is an autosomal dominant disorder leading to degeneration of neurons in the cerebellum and in other cell populations in the CNS. It belongs to the group of neurodegenerative disorders caused by expansion of a polyglutamine (polyQ) repeat. Neither symptomatic nor neuronprotective agents have been identified for the treatment of human neurodegenerative ataxias. In the previous funding period we defined the calcium channel subunit CACNA1A (Cav2.1) and the parkin E3 ubiquitin ligase as modifiers of the SCA2 phenotype in vitro and in humans. Based on these findings, we will test the following hypotheses making use of mouse lines expressing knockout or knockin alleles for the two genes: 1) Cav2. 1 modulates the motor and morphologic phenotypes of SCA2-transgenic mice. 2) The molecular mechanism is related to loss of function and sequestration of Cav2.1 subunits into aggregates or due to altered calcium channel function in the presence of mutant ataxin-2. We hypothesize that different modifier mechanisms may underlie neuronal dysfunction and neuronal death. 3) Decreasing parkin expression will enhance pathogenicity of mutant ataxin-2 by increasing ataxin-2 steady-state levels. To test these hypotheses, we will use our SCA2 transgenic model, which targets expression of mutant ataxin-2[Q58] to cerebellar Purkinje cells and replicates salient features of the human disease such as progressive functional loss and morphologic alterations in the cerebellum. We will also generate novel mouse lines expressing ataxin-2 under control of SCA2 regulatory elements. In the first aim, we will cross SCA2 transgenic mice with lines that express Cacna1a knock-out or Cacna1a[Q30] or [Q84]- knockin alleles. Mice will be evaluated by functional testing, morphologic analysis, and physiology using the cerebellar slice preparation. We will differentiate effects on disease initiation and on progression by determining age of onset as well as parameters of morphologic and behavioral progression in the resulting crosses. In the second aim, we will cross parkin null mice with SCA2 transgenic mice and examine whether loss of parkin in vivo accelerates motor dysfunction and morphologic changes. We will also determine whether overexpression of parkin delays disease onset by crossing SCA2 transgenic mice with mice overexpressing parkin in Purkinje cells. The proposed experiments address two significant questions relating to SCAs: the importance of ion channels in cerebellar dysfunction and neuronal death in the presence of mutant polyQ proteins and feasibility and effects of down-regulating ataxin-2 by modulating E3 ligase function.

Public Health Relevance

Neurodegenerative diseases are imposing an increasing health and financial burden given the rapid increase of the aging segment of the population. The spinocerebellar ataxias are inherited neurodegenerative disorders affecting brain circuits involved in movement coordination. In the previous funding cycle, we have identified modifiers of SCA neurodegeneration. We are now proposing to test the precise mechanisms underlying disease modification making use of mouse models. This will allow us to test the effects of specific proteins on nerve cell dysfunction and cell death in live animals with the ultimate goal of identifying new therapeutic avenues for treatment of human neurodegenerative diseases.

Agency
National Institute of Health (NIH)
Institute
National Institute of Neurological Disorders and Stroke (NINDS)
Type
Research Project (R01)
Project #
5R01NS033123-11
Application #
7870280
Study Section
Cell Death in Neurodegeneration Study Section (CDIN)
Program Officer
Gwinn, Katrina
Project Start
1996-02-01
Project End
2013-06-30
Budget Start
2010-07-01
Budget End
2011-06-30
Support Year
11
Fiscal Year
2010
Total Cost
$328,337
Indirect Cost
Name
University of Utah
Department
Neurology
Type
Schools of Medicine
DUNS #
009095365
City
Salt Lake City
State
UT
Country
United States
Zip Code
84112
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Scoles, Daniel R; Pulst, Stefan M (2018) Spinocerebellar Ataxia Type 2. Adv Exp Med Biol 1049:175-195
Scoles, Daniel R; Meera, Pratap; Schneider, Matthew D et al. (2017) Antisense oligonucleotide therapy for spinocerebellar ataxia type 2. Nature 544:362-366
Meera, Pratap; Pulst, Stefan; Otis, Thomas (2017) A positive feedback loop linking enhanced mGluR function and basal calcium in spinocerebellar ataxia type 2. Elife 6:
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Graf, Julia; Hellenbroich, Yorck; Veelken, Norbert et al. (2016) Two different genetic diseases in the same patient: Coincident, concomitant, or causally related? Mov Disord 31:491-2
Dansithong, Warunee; Paul, Sharan; Figueroa, Karla P et al. (2015) Ataxin-2 regulates RGS8 translation in a new BAC-SCA2 transgenic mouse model. PLoS Genet 11:e1005182
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