# Spinal muscular atrophy: Mechanisms and treatment strategies

> **NIH NIH R01** · COLUMBIA UNIVERSITY HEALTH SCIENCES · 2020 · $384,491

## Abstract

Abstract
Abnormal accumulation of the tau protein in cerebral neurons contributes to the pathogenesis of more than a
dozen neurodegenerative diseases, most notably Alzheimer’s disease (AD). Individuals afflicted with these
tauopathies have little therapeutic recourse. Preventing tau deposition or promoting its clearance is one
intuitively appealing treatment approach. Here we propose to explore one such strategy. The proposal is in
response to an FOA described in NOT-AG-20-008 and serves as a supplement to our parent project - Spinal
muscular atrophy (SMA): Mechanisms and treatment strategies (R01 NS1042108). SMA, a common
monogenic motor neuron disorder caused by low SMN protein, constitutes an excellent paradigm to study
general mechanisms underlying selective neuronal loss in common human diseases. While pursuing the
objectives of our parent project, we discovered a potent genetic modulator of the SMA phenotype. Transgenic
expression of the modulator arrests motor neuron loss and turns a severe SMA phenotype into a decidedly
mild one. Interestingly, the modulator, a variant of a synaptic chaperone known to play a role in neuronal
proteostasis is also reported to govern tau stability and function. In cultured cells, inhibiting the chaperone was
found to aid in the removal of tau by the proteasome. This effect on tau dynamics has, however, not been
investigated in the intact organism. Here we wish to address this critically important and clinically relevant gap
in our understanding of tau biology. To do so we will employ the rTg(tauP301L)4510 rodent model. We will
introduce onto this mutant background the chaperone variant and determine if and how disease in this model
of AD is altered when the chaperone is constitutively expressed. We will also determine the course of disease
in the model when the variant chaperone is delivered – by means of a viral vector – following symptom onset.
We hypothesize that the variant form of the chaperone promotes tau triage for degradation in the proteasome.
Accordingly, we expect it to mitigate the disease phenotype of the rTg4510 mice. A modification of disease in
the mutants will be of dual consequence. First, it will constitute important proof-of-concept of one potentially
useful means of treating AD and other tau-related dementias. Moreover, it will reveal a novel therapeutic target
for combating the devastating effects of this class of neurodegenerative disease.

## Key facts

- **NIH application ID:** 10123171
- **Project number:** 3R01NS104218-02S1
- **Recipient organization:** COLUMBIA UNIVERSITY HEALTH SCIENCES
- **Principal Investigator:** Umrao Monani
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2020
- **Award amount:** $384,491
- **Award type:** 3
- **Project period:** 2020-07-01 → 2020-11-30

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10123171

## Citation

> US National Institutes of Health, RePORTER application 10123171, Spinal muscular atrophy: Mechanisms and treatment strategies (3R01NS104218-02S1). Retrieved via AI Analytics 2026-05-25 from https://api.ai-analytics.org/grant/nih/10123171. Licensed CC0.

---

*[NIH grants dataset](/datasets/nih-grants) · CC0 1.0*