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Principal Investigator: Paras Patel
Organization: VIRGINIA POLYTECHNIC INST AND ST UNIV
Fiscal Year: 2021
Award: $39,800
Funding agency: National Institute of Neurological Disorders and Stroke
PROJECT SUMMARY
Understanding how different regions of the central nervous system (CNS) are affected by genetic insults is critical
to advancing the study of CNS pathologies which present a major public health burden in the United States. The
cerebellum and optic nerve are two such regions that are disproportionately hypoplastic in the majority of cases
of CASK gene mutation in humans. CASK is an enigmatic multi-domain scaffolding protein which plays a vital
role in organizing protein complexes at the pre-synapse through interactions with both active zone proteins and
trans-synaptic adhesion molecules such as liprins-α and neurexins. Mutations in the X-linked CASK gene in
humans are largely post-natally lethal in the hemizygous condition and result in microcephaly with pontine and
cerebellar hypoplasia (PCH) as well as optic nerve hypoplasia (ONH) in heterozygous mutations.
While CASK has been traditionally regarded as playing a role in CNS development, recent data indicate
that it plays a continued role in the maintenance of the adult CNS. Specifically, acute global deletion of Cask in
adult mice using a CreER-Tamoxifen system leads to progressive degeneration in motor coordination
culminating in profound ataxia several months after tamoxifen injection. This coincides with a progressive
deterioration of cerebellar gross morphology. Thus, this presents a unique opportunity to understand the
continued role of a gene, previously regarded as developmentally important, in the function of the adult CNS and
how this function may differ in a region-specific manner.
Recently, it has been demonstrated that progression of ONH in the context of CASK-loss is non-cell
autonomous in nature as deleting Cask from retinal ganglion cells themselves does not exacerbate ONH, but
deleting it from fibrous astrocytes of the optic nerve does exacerbate ONH. However, when Cask is deleted
specifically in granule cells (GCs) using a Calb2 promoter driven Cre recombinase, there appears to be a cell-
autonomous death of GCs. This provides an opportunity to examine how underlying etiopathology and functional
loss differ in two regions given the same genetic insult. As granule cells are the major excitatory driver of the
cerebellum, this project will investigate the progression of granule cell loss, the correlation of granule cell loss to
functional motor loss and ataxia, and the electrophysiological implications of loss of the major excitatory driver
in an isolated brain region. Further, the project will elucidate whether aberrations in spike-timing and frequency
among cerebellar Purkinje cells precede or follow anatomical reductions in granule cell number. The project will
also examine whether visual function correlates to optic nerve diameter in models which display ONH but not
PCH and vice versa using visual evoked potential recordings from V1 of visual cortex and the dorsal lateral
geniculate nucleus of the thalamus. Finally, the study will determine molecular mechanisms of non-apoptotic or
apoptotic cell death underlying loss of GCs. Thus, the study will investigate differing causes and functional
consequences with region-specificity in the context of a single genetic insult using Cask deletion as a test-case.
Terms: <21+ years old><ARHGEF5><ARHGEF5 gene><Active Oxygen><Acute><Adhesion Molecule><Adult><Adult Human><Affect><Anatomic><Anatomic Sites><Anatomic structures><Anatomical Sciences><Anatomy><Apoptosis><Apoptosis Pathway><Apoptotic><Astroprotein><Ataxia><Ataxy><Atrophic><Atrophy><Brain><Brain Nervous System><Brain region><CNS Nervous System><CRE Recombinase><Caliber><Cell Adhesion Molecule Gene><Cell Adhesion Molecules><Cell Body><Cell Count><Cell Death><Cell Function><Cell Number><Cell Process><Cell physiology><Cells><Cellular Function><Cellular Physiology><Cellular Process><Cellular Stress><Central Nervous System><Cerebellar degeneration><Cerebellar hypoplasia><Cerebellum><Cessation of life><Chronic><Congenital cerebellar hypoplasia><Coordination Impairment><Cranial Nerve II><DNA Alteration><DNA Nucleotidylexotransferase><DNA Sequence Alteration><DNA mutation><Data><Death><Deoxynucleotidyl Transferase><Deoxynucleotidyltransferase><Desoxynucleotidyl Transferase><Desoxynucleotidyltransferase><Deterioration><Development><Diameter><Dorsal><Dysfunction><Dyssynergia><Electrons><Electrophysiology><Electrophysiology (science)><Encephalon><Enterobacteria phage P1 Cre recombinase><Evoked Potentials><Fe element><Fibrous Astrocyte><Frequencies><Functional disorder><GEF5><GFA-Protein><GFAP><Gene Alteration><Gene Mutation><Genes><Genetic><Genetic Alteration><Genetic Change><Genetic Diseases><Genetic defect><Genetic mutation><Glial Fibrillary Acid Protein><Glial Fibrillary Acidic Protein><Glial Intermediate Filament Protein><Human><Image><Impairment><In Situ Hybridization><In Situ Nick-End Labeling><Individual><Injections><Iron><KO mice><Knock-out Mice><Knockout Mice><Label><Lateral Geniculate Body><Lead><Leanness><Length of Life><Link><Lipid Peroxidation><Lipids><Longevity><Lycopersicon esculentum><Lyonization><Maintenance><Measures><Mediating><Mice><Mice Mammals><Microcephaly><Microscopy><Modeling><Modern Man><Molecular><Morphology><Mosaicism><Motor><Murine><Mus><Mutation><Nature><Necrosis><Necrotic><Negative Beta Particle><Negatrons><Nerve Degeneration><Nervous System Diseases><Nervous System Physiology><Neuraxis><Neurologic Disorders><Neurologic function><Neurological Disorders><Neurological function><Neurology><Neuron Degeneration><Neurophysiology / Electrophysiology><Null Mouse><Optic Nerve><Oxidative Stress><Oxygen Radicals><P-30 Protein><P30><P30 Protein><P60><Pathogenicity><Pathologic><Pathology><Pathway interactions><Pb element><Personal Satisfaction><Phenotype><Photons><Physiologic><Physiological><Physiology><Physiopathology><Play><Pons><Pons Cerebelli><Pons Varolii><Pontine><Pontine structure><Pontocerebellar hypoplasia><Pro-Oxidants><Productivity><Programmed Cell Death><Property><Proteins><Public Health><Purkinje Cells><Purkinje's Corpuscles><RIP3><RIPK3><RIPK3 gene><Reactive Oxygen Species><Receptor-Interacting Protein 3><Receptor-Interacting Serine/Threonine Protein Kinase 3><Retina><Retinal Ganglion Cells><Role><Scaffolding Protein><Second Cranial Nerve><Sequence Alteration><Sight><Slice><Solanum lycopersicum><Specificity><Staining method><Stains><Stress><Subcellular Process><Synapses><Synaptic><System><TIM1><TUNEL><Tamoxifen><Terminal Addition Enzyme><Terminal Deoxynucleotidyl Transferase><Terminal Deoxynucleotidyltransferase><Terminal Deoxyribonucleotidyl Transferase><Terminal Deoxyribonucleotidyltransferase><Testing><Thalamic structure><Thalamus><Thinness><Time><Tomatoes><United States><Vision><Visual><Visual Cortex><Visual Evoked Potentials><Visual Evoked Response><Visual System><Visual evoked cortical potential><Visual system structure><X Inactivation><X-Chromosome Inactivation><adulthood><awake><bacteriophage P1 recombinase Cre><base><brain volume><cell adhesion protein><cell stress><cell type><cerebellar Purkinje cell><cerebellum degeneration><developmental><electrophysiological><functional loss><genetic condition><genetic disorder><genome mutation><genomic alteration><granule cell><heavy metal Pb><heavy metal lead><imaging><in situ Hybridization Genetics><in situ Hybridization Staining Method><lateral geniculate><lateral geniculate nucleus><life span><lifespan><micrencephaly><microencephaly><mosaic disorders><mouse model><murine model><necrocytosis><nervous system development><nervous system disorder><nervous system function><neural degeneration><neurodegeneration><neurodegenerative><neurological degeneration><neurological disease><neuronal degeneration><neurophysiological><neurophysiology><oxidation><pathophysiology><pathway><postnatal><promoter><promotor><protein complex><ranpirnase><retinal ganglion><social role><synapse><terminal nick end labeling><thalamic><translational neuroscience><visual cortical><visual function><well-being><wellbeing>