Abstract

TDP-43 is required for splicing of Stathmin-2 (STMN2) transcript, so STMN2 is reduced in most ALS patients. TDP-43 does not regulate STMN2 in mice as it does in humans. Thus, mouse models of ALS do not reflect patient loss of STMN2. To test the hypothesis that a reduction in STMN2 contributes to ALS pathogenesis, we generated STMN2 knockout mice. Constitutive STMN2 loss induces an early sensory and motor neuropathy with disrupted motor behavior and dramatic distal neuromuscular junction (NMJ) denervation. This NMJ pathology occurs in fast-fatigable motor units, which are the most vulnerable in ALS. In contrast, motoneurons and axons do not degenerate. STMN2 heterozygous mice better model the partial loss of STMN2 protein occurring in ALS patients. This mild reduction in STMN2 causes a progressive, motor-selective neuropathy with functional deficits and NMJ denervation. Moreover, combining partial STMN2 depletion with a gain of function TDP-43 allele, TDP-43Q331K, resulted in a progressive motor-selective deficit. While no neurodegeneration is observed when deficits first present, mitochondria in distal axons show signs of severe pathology indicating that neurons maybe be metabolically unstable and dysfunctional. Thus, our findings strongly support the hypothesis that STMN2 reduction due to TDP-43 pathology contributes to ALS pathogenesis.

Committee Chair

Aaron DiAntonio

Committee Members

Christopher Lucas; Jacob Montgomery; Leticia Bode; Sunita Parikh

Degree

Doctor of Philosophy (PhD)

Author's Department

Biology & Biomedical Sciences (Neurosciences)

Author's School

Graduate School of Arts and Sciences

Document Type

Dissertation

Date of Award

4-3-2025

Language

English (en)

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