In most inherited degenerative ataxias, selective loss of certain types of neurons occurs primarily in the cerebellum and brain stem despite widespread expression of the disease protein. Many of these selectively vulnerable neurons exhibit autonomous pacemaker firing. Neuronal dysfunction must precede the eventual loss of neurons in ataxia, but the nature of this neuronal dysfunction and its causal relationship to motor symptoms are not well established. My preliminary studies in a mouse model of the polyglutamine disorder Spinocerebellar Ataxia Type 3 (SCA3) have identified altered firing properties of one class of pacemaker neurons, the cerebellar Purkinje neurons, and have shown that transiently correcting this aberrant physiology with a potassium channel activator improves the motor phenotype in SCA3 mice. The studies proposed here, which take advantage of my expertise in electrophysiology and will be performed in a leading SCA3 laboratory, will test the hypothesis that the selective neuronal vulnerability observed in SCA3, and possibly other polyglutamine ataxias, reflects alterations in the properties of neuronally expressed potassium channels. The proposal has 3 aims.
Aim 1 will examine the firing properties of various affected pacemaker neurons in SCA3 and determine whether alterations in potassium channel physiology can explain the observed changes in firing properties.
Aim 2 will determine the mechanism for polyglutamine disease protein-induced changes in potassium channel biophysics.
Aim 3 will examine whether modulators of potassium channel physiology can improve the motor symptoms in SCA3 mice. The overall objective of these studies is to determine whether such physiologic changes are promising targets for symptomatic or preventive treatment of these currently untreatable disorders. The impact of these studies will be to move the field of degenerative ataxias, which has focused primarily on changes in brain morphology and biochemistry, towards looking at specific, early and potentially modifiable changes in neuronal function. My career goal over the next five years is to become an independent researcher with the expertise to investigate the physiologic underpinnings of SCA3 and related ataxias and to design and test pharmacologic agents that can serve as a route to therapy for these currently untreatable disorders. My long term goal is to secure and succeed in a tenure-track faculty position at a neurology department at a major institution, combining the care of patients with movement disorders and heading a research laboratory that continues to interrogate the role of ion-channels in the pathogenesis of degenerative ataxic disorders.

Public Health Relevance

Spinocerebellar ataxia type 3 (SCA3), the most common dominantly inherited form of ataxia, causes loss of balance and coordination in patients and is associated with a loss of nerve cells in certain brain regions, notably the cerebellum and brain stem. This proposal examines whether correcting perturbations in the electrical properties of nerve cells in these affected brain regions in SCA3 will lead to the development of new drugs to treat this currently untreatable, fatal disorder. Project Narrative Spinocerebellar ataxia type 3 (SCA3), the most common dominantly inherited form of ataxia, causes loss of balance and coordination in patients and is associated with a loss of nerve cells in certain brain regions, notably the cerebellum and brain stem. This proposal examines whether correcting perturbations in the electrical properties of nerve cells in these affected brain regions in SCA3 will lead to the development of new drugs to treat this currently untreatable, fatal disorder.

Agency
National Institute of Health (NIH)
Type
Clinical Investigator Award (CIA) (K08)
Project #
5K08NS072158-05
Application #
8706243
Study Section
Neurological Sciences Training Initial Review Group (NST)
Program Officer
Gwinn, Katrina
Project Start
Project End
Budget Start
Budget End
Support Year
5
Fiscal Year
2014
Total Cost
Indirect Cost
Name
University of Michigan Ann Arbor
Department
Neurology
Type
Schools of Medicine
DUNS #
City
Ann Arbor
State
MI
Country
United States
Zip Code
48109
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
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
Costa, Maria do Carmo; Luna-Cancalon, Katiuska; Fischer, Svetlana et al. (2013) Toward RNAi therapy for the polyglutamine disease Machado-Joseph disease. Mol Ther 21:1898-908
Shakkottai, Vikram G; Fogel, Brent L (2013) Clinical neurogenetics: autosomal dominant spinocerebellar ataxia. Neurol Clin 31:987-1007
Yu, Ting; Shakkottai, Vikram G; Chung, Chan et al. (2011) Temporal and cell-specific deletion establishes that neuronal Npc1 deficiency is sufficient to mediate neurodegeneration. Hum Mol Genet 20:4440-51