# Determining stathmin-2 function and potential as a therapeutic target in ALS/FTD

> **NIH NIH R01** · LUDWIG INSTITUTE  FOR CANCER RES  LTD · 2022 · $797,269

## Abstract

Cytoplasmic protein accumulations of the RNA/DNA binding protein TDP-43 are found in affected neurons in
almost all instances of amyotrophic lateral sclerosis (ALS) and approximately 50% of frontotemporal
dementia (FTD). Nuclear clearance of TDP-43 has been widely observed in affected neurons in sporadic
ALS/FTD, evidence strongly supporting the proposal that TDP-43 loss of function is a key aspect of disease
mechanism underlying ALS/FTD pathogenesis. We have identified that the mRNA encoding stathmin-2 is 1) an
essential factor for axonal regeneration of axotomized iPSC-derived motor neurons and 2) the mRNA most
affected by reduction in TDP-43 function, with a striking loss from motor neurons in sporadic ALS and inherited
disease from GGGGCC expansion in C9orf72. Stathmin-2 is an abundant, direct binding partner of α/β-tubulin
dimers in neuronal perikarya, axons, growth cones, and synapses, including neuromuscular junctions (NMJs).
Using genome editing, we will identify the mechanism of TDP-43-dependent premature polyadenylation/cryptic
splicing that suppresses stathmin-2 synthesis when TDP-43 levels are lowered. We will use genome editing of
induced pluripotent stem cells (iPSCs) derived human motor neurons grown in compartmented chambers (that
separate neuronal cell bodies, axons and growth cones) to determine how stathmin-2 functions in a) motor
neuron maintenance/repair, b) axonal microtubule stabilization and/or dynamics, c) neuromuscular junction
formation and/or stabilization, and d) how palmitoylation of stathmin-2 affects its axonal function(s). Genome
wide CRISPR/Cas9 screens using flow cytometry and optical methods will be undertaken to identify factors that
control stathmin-2 synthesis or accumulation. Finally, we will determine the consequences in mice of reduction
or loss of stathmin-2 on motor neuron function and muscle innervation/denervation and whether reduction in
stathmin-2 synergizes with TDP-43 mutation to drive motor neuron disease. Outcomes of these efforts will
provide key insights for understanding basic aspects of axonal and synaptic neurobiology and for evaluating
whether maintaining or restoring stathmin-2 is an attractive therapeutic option in sporadic ALS/FTD and
ALS from its most frequent genetic cause, repeat expansion in C9orf72.

## Key facts

- **NIH application ID:** 10370327
- **Project number:** 5R01NS112503-03
- **Recipient organization:** LUDWIG INSTITUTE  FOR CANCER RES  LTD
- **Principal Investigator:** Don W Cleveland
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2022
- **Award amount:** $797,269
- **Award type:** 5
- **Project period:** 2020-04-01 → 2025-03-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10370327

## Citation

> US National Institutes of Health, RePORTER application 10370327, Determining stathmin-2 function and potential as a therapeutic target in ALS/FTD (5R01NS112503-03). Retrieved via AI Analytics 2026-05-23 from https://api.ai-analytics.org/grant/nih/10370327. Licensed CC0.

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