Keywords

IGHMBP2, CMT, motoneuron, iPSC, paralysis, CMT2s

Abstract

Charcot-Marie-Tooth (CMT) disease is the most common inherited peripheral neuropathy, affecting 2.6 million people globally. CMT2s is a type of CMT that is caused by a heterogeneous mutation in the immunoglobulin μ-binding protein 2 (IGHMBP2) gene, which is involved in helicase binding. This results in the deterioration of motor and sensory function in the lower extremities. Ultimately, this impacts the neuromuscular junction (NMJ), a crucial component for motor function, resulting in progressive paralysis in most instances. Currently, studies aimed at CMT investigation and therapeutic development rely heavily on animal models, which frequently demonstrate difficulties in translation while being expensive and time-consuming. For this reason, an in vitro model was developed by differentiating motoneurons from patient-derived induced pluripotent stem cells (iPSCs), with which the pathology was investigated. This phenotypic analysis includes the use of immunocytochemistry to examine axonal varicosity formation and axonal growth and branching, patch clamp techniques to assess electrophysiological function, and tetramethylrhodamine ethyl ester (TMRE) staining to evaluate mitochondrial integrity. The results showed a functional loss for CMT2s primarily at late stages, starting around week two in vitro and then continuing to decline to the point of widespread cell death. These phenotypes correlate with clinical pathologies reported from the CMT2s patient. This patient-derived iPSC-MN model will provide essential tools for CMT2s pathogenesis studies and drug development.

Completion Date

2024

Semester

Spring

Committee Chair

Guo, Xiufang

Degree

Master of Science (M.S.)

College

College of Graduate Studies

Department

Nanoscience Technology Center

Degree Program

Nanotechnology MS

Format

application/pdf

Language

English

Rights

In copyright

Release Date

November 2027

Length of Campus-only Access

3 years

Access Status

Doctoral Dissertation (Campus-only Access)

Campus Location

Orlando (Main) Campus

Accessibility Status

Meets minimum standards for ETDs/HUTs

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Restricted to the UCF community until November 2027; it will then be open access.

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