Vikram G. Shakkottai, Ph.D. - US grants

DESCRIPTION (provided by applicant): 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.

Abstract 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.