Cerebellar ataxias, a group of disabling and untreatable neurodegenerative disorders affecting up to 150,000 people in the United States, result in uncoordinated limb and trunk movements and falls, frequently leading to wheelchair confinement. At the cellular level, the ataxias are primarily associated with neuronal loss within the cerebellum and its associated pathways. Neuronal dysfunction precedes and accompanies neuronal loss and contributes to motor symptoms, but the mechanisms responsible for these early events are poorly understood. In Spinocerebellar Ataxia type 1 (SCA1), the best studied and one of the more common dominantly inherited ataxias, a reduction in cerebellar Purkinje neuron cell size and dendritic arborization precedes overt neuronal loss, as in other ataxias. Building on our prior work establishing that electrophysiological dysfunction of cerebellar neurons contributes to motor deficits in different mouse models of ataxia, we now seek to determine whether changes in Purkinje neuron function contribute to altered morphology and motor dysfunction in SCA1. Purkinje neurons generate autonomous, pacemaker action potentials even in the absence of synaptic input. Our preliminary data in a mouse model of SCA1 demonstrate that Purkinje neuron pacemaker firing is initially normal, but by 5 weeks of age, pacemaker firing is disrupted, together with abnormal depolarization of membrane potential associated with reduced activity of subthreshold-activated potassium channels. Strikingly, subsequent Purkinje cell shrinkage is associated with relative restoration of pacemaker firing, indicating that cell shrinkage may reflect the attempt of Purkinje neurons to compensate for physiologic dysfunction. We hypothesize that abnormal activity of subthreshold-activated potassium channels is a critical early event in the pathogenesis of SCA1. We also hypothesize that compensatory mechanisms to maintain normal Purkinje pacemaker firing contribute to cell shrinkage - which is actually beneficial - but that failure of this compensation leads to neurodegeneration. In the following specific aims we propose to test these hypotheses at the cell and circuit level, and to explore whether preventing potassium channel dysfunction will ameliorate neurodegeneration and motor dysfunction. The project has three aims.
Aim 1 will determine the mechanism underlying membrane depolarization in SCA1 Purkinje neurons.
Aim 2 will determine the consequences of Purkinje neuron atrophy on cerebellar circuitry, and aim 3 will determine whether maintaining normal membrane potential will prevent Purkinje neuron atrophy and improve motor symptoms in SCA1 transgenic mice.

Public Health Relevance

Spinocerebellar ataxia type 1 (SCA1), the most extensively studied and one of the more common dominantly inherited forms of ataxia, causes loss of balance and coordination in patients and is associated with a loss of nerve cells in certain in the cerebellum and its associated pathways. This proposal examines whether correcting perturbations in the electrical properties of nerve cells in the cerebellum in SCA1 and possibly other degenerative ataxias will lead to the development of new drugs to treat this currently untreatable disorder.

Agency
National Institute of Health (NIH)
Institute
National Institute of Neurological Disorders and Stroke (NINDS)
Type
Research Project (R01)
Project #
1R01NS085054-01
Application #
8610842
Study Section
Cellular and Molecular Biology of Neurodegeneration Study Section (CMND)
Program Officer
Gwinn, Katrina
Project Start
2013-09-30
Project End
2018-06-30
Budget Start
2013-09-30
Budget End
2014-06-30
Support Year
1
Fiscal Year
2013
Total Cost
$325,250
Indirect Cost
$110,197
Name
University of Michigan Ann Arbor
Department
Neurology
Type
Schools of Medicine
DUNS #
073133571
City
Ann Arbor
State
MI
Country
United States
Zip Code
48109
Shakkottai, Vikram G (2014) Physiologic changes associated with cerebellar dystonia. Cerebellum 13:637-44
Chopra, Ravi; Shakkottai, Vikram G (2014) Translating cerebellar Purkinje neuron physiology to progress in dominantly inherited ataxia. Future Neurol 9:187-196
Chopra, Ravi; Shakkottai, Vikram G (2014) The role for alterations in neuronal activity in the pathogenesis of polyglutamine repeat disorders. Neurotherapeutics 11:751-63
Luna-Cancalon, Katiuska; Sikora, Kristine M; Pappas, Samuel S et al. (2014) Alterations in cerebellar physiology are associated with a stiff-legged gait in Atcay(ji-hes) mice. Neurobiol Dis 67:140-8