Intracellular Fibroblast Growth Factor 14 (iFGF14) is a novel accessory subunit of voltage gated sodium (Nav) channels9-11 that is linked to spinal cerebellar ataxia 27 (SCA27)3, a debilitating disease, associated with progressive ataxia and mental decline. Previous work in cultured neurons and heterologous expression systems demonstrate that iFGF14 binds to the C-termini of Nav channel pore forming (?) subunits and modulates the properties of the fast transient Nav currents underlying action potentials5,13. iFGF14 is expressed as two N-terminal splice variants in multiple cell types throughout the central nervous system2,4,5. Deletion or knock-down of iFGF14 has recently been shown to attenuate excitability in cerebellar granule and Purkinje neurons7-8, though, an understanding of how iFGF14 regulates excitability in these cell types or its effect on behavior is lacking. The goa of the proposed research is to determine the effect and role of each iFGF14 splice variant in regulating intrinsic excitability of cerebellar neurons; and, to define how dysfunction of iFGF14 expression in cerebellar neurons can result in deleterious phenotypes. To do this, I will utilize viral vectors for acute expression, or knock-down, of iFGF14 in distinct classes of mouse cerebellar neurons. I will also utilize a newly generated mouse model with a knockin SCA27 causing human mutation FGF14145S. With these experimental systems, I will investigate effects of iFGF14 on Nav currents and intrinsic excitability in cerebellar Purkinje and granule neurons from intact slices. I will complete parallel experiments to define the effects of iFGF14 on mouse balance and motor coordination. The results of the proposed experiments will move our understanding of iFGF14 function forward and provide new insights into the mechanisms underlying SCA27 pathophysiology.

Public Health Relevance

Electrical activity in neurons is dependent on the expression and functioning of ion channels that mediate the influx and efflux of ions across membranes. Normal physiology is dependent on proper functioning of these ion channels and dysfunction of ion channels is associated with neurological disorders19-20. The focus of this proposal is on the protein intracellular fibroblast growth factor 14 (iFGF14) that has recently been linked to the inherited neurological disease SCA273 and is known to regulate the activity of one population of ion channels9-11 important in generating functional electrical activity in neurons. The purpose of this proposal is to determine the underlying cellular and molecular mechanisms by which this protein affects neuronal electrical activity.

Agency
National Institute of Health (NIH)
Institute
National Institute of Neurological Disorders and Stroke (NINDS)
Type
Postdoctoral Individual National Research Service Award (F32)
Project #
5F32NS090765-03
Application #
9177773
Study Section
Special Emphasis Panel (ZRG1)
Program Officer
Miller, Daniel L
Project Start
2014-12-01
Project End
2017-11-30
Budget Start
2016-12-01
Budget End
2017-11-30
Support Year
3
Fiscal Year
2017
Total Cost
Indirect Cost
Name
Washington University
Department
Internal Medicine/Medicine
Type
Schools of Medicine
DUNS #
068552207
City
Saint Louis
State
MO
Country
United States
Zip Code
63130
Ransdell, Joseph L; Dranoff, Edward; Lau, Brandon et al. (2017) Loss of Nav?4-Mediated Regulation of Sodium Currents in Adult Purkinje Neurons Disrupts Firing and Impairs Motor Coordination and Balance. Cell Rep 19:532-544
Bosch, Marie K; Carrasquillo, Yarimar; Ransdell, Joseph L et al. (2015) Intracellular FGF14 (iFGF14) Is Required for Spontaneous and Evoked Firing in Cerebellar Purkinje Neurons and for Motor Coordination and Balance. J Neurosci 35:6752-69
Victor, Matheus B; Richner, Michelle; Hermanstyne, Tracey O et al. (2014) Generation of human striatal neurons by microRNA-dependent direct conversion of fibroblasts. Neuron 84:311-23