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Paras Patel's Dissertation Defense (5/5/2022): The Role of CASK in Central Nervous System Function and Disorder

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Paras Patel

Dissertation Defense: The Role of CASK in Central Nervous System Function and Disorder

Paras Patel

Graduate Student, Translational Biology, Medicine, and Health
Graduate Research Assistant, Mukherjee Lab, Fralin Biomedical Research Institute at VTC
May 5, 2022 at 10:00 a.m.
Room G101B, 4 Riverside Circle, Fralin Biomedical Research Institute at VTC

About this Dissertation

Understanding how different regions of the central nervous system (CNS) are affected by genetic insults is critical to advancing the study of CNS pathologies. The cerebellum is one such region which is 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) and also optic nerve hypoplasia (ONH) in heterozygous mutations. Herein, Patel, mentored by Dr. Konark Mukherjee, used various molecular and genetic strategies to uncover the role of the CASK protein in brain function and pathogenesis of cerebellar hypoplasia associated with CASK mutations/deletions. First, using the face- and construct-validated heterozygous CASK knockout (Cask+/-) murine model, Patel conducted bulk RNA-sequencing and proteomics experiments from whole brain lysates to uncover changes in the Cask+/- brain. RNA-sequencing revealed the majority of changes to be broadly categorized into metabolic, nuclear, synaptic, and extracellular- matrix associated transcripts. Proteomics revealed the majority of changes cluster as synaptic proteins, metabolic proteins, and ribosomal subunits. Thus, absence of CASK in half of brain cells seems to affect synaptic protein content, cell metabolism, and protein homeostasis. Extending these observations, Patel conducted GFP-trap immunoprecipitation followed by tandem mass spectroscopy to reveal protein complexes in which CASK participates. Commensurate with proteomic changes, CASK was found to complex with synaptic proteins, metabolic proteins, cytoskeletal elements, ribosomal subunits, and protein folding machinery. Next, in order to investigate the pathogenesis of CASK-linked cerebellar hypoplasia, Patel utilized a human case of early truncation wherein the 27th arginine of CASK is converted to a stop codon. Immunohistochemical analysis of this brain revealed an upregulation of glial fibrillary acidic protein, a common marker for degenerative cell death. To mechanistically test the hypothesis that cerebellar hypoplasia results from cell death rather than developmental failure, Patel created a murine model wherein CASK is deleted from the majority of cerebellar cells post-development using Cre recombinase driven by the Calb2 promoter. Deleting CASK from all cerebellar granule neurons post-migration indeed leads to degeneration of the cerebellum via massive depletion of granule cells while sparing Purkinje cells. Overall, the cerebellum shrinks by approximately half in cross-sectional area and degeneration is accompanied by a collapsing of the molecular layer and of Purkinje cell dendrites. In addition, cerebellar degeneration presents with a profound locomotor ataxia. In conclusion, CASK seems to be affecting brain energy homeostasis and synaptic connections via interactions with metabolic proteins, synaptic proteins, and protein homeostatic elements. Further, alterations in brain volume associated with CASK-linked disorders is the result of degenerative cell death rather than developmental failure as previously posited.

More About the Candidate and Project


Virginia Tech, Translational Biology, Medicine, and Health, Ph.D. Candidate

Wake Forest University, B.S., Biology


Graduate Research Assistant, Mukherjee Lab



Konark Mukherjee, Ph.D., MBBS, Assistant Professor, Fralin Biomedical Research Institute at VTC

Committee Members

  • NIH Ruth L. Kirschstein National Research Service Award (NRSA) F31 NS120584-01A1 - 2021
  • Society for Neuroscience Trainee Professional Development Award 2021
  • American Society for Neurochemistry Young Investigator Educational Enhancement 2021
  • NPGA Flash Talks best seminar – Neuroscience Postdoctoral and Graduate Association 2021
  • 3rd place best poster – Central Virginia Chapter of the Society for Neuroscience Meeting 2019
  • Research!America Civic Engagement Microgrant 2019
  • Wake Forest University Department of Linguistics Distinguished Student 2017
  • ACC-IAC Fellows Program in Creativity and Innovation Grant 2015
  • Wake Forest University Dean’s List Fall 2013, Fall 2014, Spring 2015
  • Wake Forest School of Business Center for Leadership and Character Distinction 2015


Patel PA, Hegert J, Cristian I, Kerr A, LaConte LEW, Fox MA, Srivastava S, Mukherjee K. 2021. “Complete loss of CASK causes severe ataxia through cerebellar degeneration in human and mouse”. Journal of Medical Genetics. Published Online First: 11 February 2022. doi: 10.1136/jmedgenet-2021-108115

Mukherjee K, Patel PA, Rajan DS, LaConte LEW, Srivastava S. 2020. “Survival of a male patient harboring CASK Arg27Ter mutation to adolescence”. Molecular Genetics and Genomic Medicine. E1426.

Patel PA, Liang C, Arora A, Vijayan S, Ahuja S, Wagley PK, Settlage R, LaConte LEW, Goodkin HP, Lazar I, Srivastava S, Mukherjee K. 2020. “Haploinsufficiency of X-Linked gene CASK induces post-transcriptional changes in synaptic and cellular metabolic pathways”. Experimental Neurology. Vol. 329: 113319.

Kerr A, Patel PA, LaConte LEW, Liang C, Chen CK, Shah V, Fox MA, Mukherjee K. 2019. “Non-Cell Autonomous Roles for CASK in Optic Nerve Hypoplasia”. Investigative Ophthalmology and Visual Science. Vol. 60(10): 3584-3594.


Patel PA, Hegert J, Cristian I, Kerr A, LaConte LEW, Fox MA, Srivastava S, English DF, Mukherjee K. “Cerebellar Abnormalities Associated with Loss of the Synaptic Scaffold CASK Follow a Degenerative Trajectory and Manifest Differentially Based on Sex”. 2021. Society for Neuroscience Meeting 2021.

Patel PA, Hegert J, Cristian I, Kerr A, LaConte LEW, Fox MA, Srivastava S, Mukherjee K. “Complete CASK Loss Causes Cerebellar Degeneration in Human and Mouse”. 2021.American Society for Neurochemistry Meeting 2021.

Patel PA. “SNPshots of the Brain: CASK as a Window into Form and Function”. 2021. Research in Progress Seminar Series.

Patel PA. “Homeostatic Trajectories and the Two Sides of CNS Development: CASK Mutations as an Exemplar”. 2020. Research in Progress Seminar Series.

Patel PA. “Diverse Functions of an Enigmatic Scaffolding Molecule”. 2020. Research in Progress Seminar Series.

Patel PA, LaConte LEW, Ahuja S, Lazar I, Mukherjee K. 2019. “Molecular Changes, Protein Complexes, and Subcellular Compartments Associated with CASK Protein and Pathology”. Translational Biology, Medicine, and Health Open House.

Patel PA, Vogelaar N, LaConte LEW, Sobrado P, Mukherjee K. 2019. “High Throughput Compound Screening for Transcriptional Manipulation in Neurological Disorders Related to CASK Mutation”. Virginia Drug Discovery Rx: Virginia Drug Discovery Consortium Symposium.

Patel PA, Mukherjee K. 2019. “Role of CASK in motor learning deficits and microcephaly”. Central Virginia Chapter of the Society for Neuroscience Annual Meeting. Poster Award

Patel PA, Olsen ML. 2018. “Finding Reliable Markers for Cortical Astrocytes and Electrophysiological Verification of Barium Sensitivity of Transfected Kir4.1/Kir5.1 Heteromers”. Translational Biology, Medicine, and Health Rotation Presentation.

Patel PA, Schuppe ER, Fuxjager MJ. 2017. “The Evolution of Multimodal Signaling in the Woodpecker Family”. Wake Forest University Department of Biology Honors Thesis Presentation.

Patel PA, Judy T. 2016. “Direct Object Pronoun Dropping in Spanish-Polish Bilinguals in the Misiones Province of Argentina”. Wake Forest University Summer Undergraduate Research Poster Symposium.


  • NeuroSURF Summer Undergraduate Research Fellowship, 2018-2019
  • Virginia Tech undergraduate students, 2018-present

Outreach and Service

  • Science Museum of Southwest Virginia LAB Chats, 2021
  • Co-founder and Co-host, Big Lick of Science Podcast, 2019-present
  • Roanoke Virginia Governor’s School Project Forum Poster Session Judge, 2019
  • Regional Science Fair Judge, 2019
  • Virginia State Science Fair Judge, 2019
  • Grandin Court Elementary School Neuroscience Outreach Demonstrator, 2019
  • Conversation Skills Workshop for International Students at Wake Forest, 2014–2017