Spinocerebellar ataxia type 13 (SCA13) is a dominant human disease characterized by locomotor problems and substantial volume loss in the cerebellum. SCA13 is caused by mutations in the KCNC3 gene, which encodes the voltage-gated K+ channel, Kv3.3. Two allelic forms of SCA13 have been described. One form emerges in adulthood and is characterized by progressive ataxia and cerebellar degeneration. The other form is evident in infancy and is characterized by severe locomotor problems, mental retardation, and cerebellar malformation. Thus, mutations in Kv3.3 are associated with both developmental and neurodegenerative phenotypes. Due to their specialized gating properties, Kv3 channels confer on neurons the ability to fire action potentials at high frequencies. Kv3 channels also control spike duration and thereby regulate activity- dependent Ca2+ influx. The two allelic forms of SCA13 are caused by different KCNC3 mutations that alter channel activity in distinct ways. The long term goal of this research is to test the hypotheses that SCA13 mutations alter the excitability of cerebellar neurons and do so in different ways, and that these changes in excitability affect the age of onset and lead to the locomotor deficits and changes in cerebellar structure that characterize the disease.
The Specific Aims of this proposal are to test the hypotheses that: 1) SCA13 mutations differentially alter the excitability of cerebellar neurons, 2) SCA13 mutations differentially alter cytoplasmic Ca2+ load in response to electrical stimulation and affect neuronal survival in Ca2+- and age- dependent cell death paradigms, and 3) the unique gating properties of Kv3 channels play a previously unsuspected role in neuronal development.
These Specific Aims will be accomplished using cerebellar neurons in vitro and a vertebrate model organism, the zebrafish Danio rerio, for electrophysiological, optical, genetic, and behavioral analysis. SCA13 is rare, but analysis of SCA13 disease mechanisms may shed light on the etiology of common neurodegenerative diseases such as Alzheimer's. Given the fact that mutations in K+ and Ca2+ channel genes lead to progressive neuronal cell death in SCA13 and SCA6, it is reasonable to suggest that changes in channel function or expression contribute to susceptibility or etiology in common neurodegenerative diseases. If changes in excitability contribute to neuronal cell death, the possibilities for prevention and treatment of neurodegenerative diseases would be greatly expanded because drugs that target specific channels and modulate excitability exist and continue to be discovered. ? ?

Agency
National Institute of Health (NIH)
Institute
National Institute of Neurological Disorders and Stroke (NINDS)
Type
Research Project (R01)
Project #
1R01NS058500-01A1
Application #
7373947
Study Section
Biophysics of Neural Systems Study Section (BPNS)
Program Officer
Tagle, Danilo A
Project Start
2007-12-15
Project End
2011-11-30
Budget Start
2007-12-15
Budget End
2008-11-30
Support Year
1
Fiscal Year
2008
Total Cost
$336,875
Indirect Cost
Name
University of California Los Angeles
Department
Physiology
Type
Schools of Medicine
DUNS #
092530369
City
Los Angeles
State
CA
Country
United States
Zip Code
90095
Hsieh, Jui-Yi; Papazian, Diane M (2018) In Vivo Analysis of Potassium Channelopathies: Loose Patch Recording of Purkinje Cell Firing in Living, Awake Zebrafish. Methods Mol Biol 1684:237-252
Hsieh, Jui-Yi; Ulrich, Brittany; Issa, Fadi A et al. (2014) Rapid development of Purkinje cell excitability, functional cerebellar circuit, and afferent sensory input to cerebellum in zebrafish. Front Neural Circuits 8:147
Issa, Fadi A; Mock, Allan F; Sagasti, Alvaro et al. (2012) Spinocerebellar ataxia type 13 mutation that is associated with disease onset in infancy disrupts axonal pathfinding during neuronal development. Dis Model Mech 5:921-9
Minassian, Natali A; Lin, Meng-Chin A; Papazian, Diane M (2012) Altered Kv3.3 channel gating in early-onset spinocerebellar ataxia type 13. J Physiol 590:1599-614
Issa, Fadi A; O'Brien, Georgeann; Kettunen, Petronella et al. (2011) Neural circuit activity in freely behaving zebrafish (Danio rerio). J Exp Biol 214:1028-38
Figueroa, Karla P; Waters, Michael F; Garibyan, Vartan et al. (2011) Frequency of KCNC3 DNA variants as causes of spinocerebellar ataxia 13 (SCA13). PLoS One 6:e17811
Leonard, Helen; Glasson, Emma; Nassar, Natasha et al. (2011) Autism and intellectual disability are differentially related to sociodemographic background at birth. PLoS One 6:e17875
Issa, Fadi A; Mazzochi, Christopher; Mock, Allan F et al. (2011) Spinocerebellar ataxia type 13 mutant potassium channel alters neuronal excitability and causes locomotor deficits in zebrafish. J Neurosci 31:6831-41
Mock, Allan F; Richardson, Jessica L; Hsieh, Jui-Yi et al. (2010) Functional effects of spinocerebellar ataxia type 13 mutations are conserved in zebrafish Kv3.3 channels. BMC Neurosci 11:99
Figueroa, Karla P; Minassian, Natali A; Stevanin, Giovanni et al. (2010) KCNC3: phenotype, mutations, channel biophysics-a study of 260 familial ataxia patients. Hum Mutat 31:191-6