# Mechanisms of Axon Pathology in ALS

> **NIH NIH R01** · COLUMBIA UNIVERSITY HEALTH SCIENCES · 2021 · $522,649

## Abstract

Amyotrophic lateral sclerosis (ALS) is a fatal paralytic disease characterized by neuromuscular junction (NMJ)
denervation that precedes spinal motor neuron (MN) death and muscle weakness. We hypothesize that
preventing denervation and stimulating reinnervation of NMJs will thwart muscle dysfunction and weakness in
ALS, hence improving the patient's quality of life and, likely extending survival. Herein, we seek to demonstrate
that protein prenylation, which was reported to operate as an endogenous brake on axonal growth, is a key
determinant of ALS-related motor axon pathology. In support of this goal, our pilot work shows that dually
silencing the prenylation enzymes, farnesyl transferase and geranylgeranyl transferase type-I, or uniquely
silencing geranylgeranyl transferase type-II, mitigates NMJ denervation in the transgenic (Tg) mouse
expressing mutant SOD1 (mSOD1). The rationale for this project is that, once it is known which prenylated
proteins are essential for ALS-related motor axon pathology and which prenyl transferases catalyze their
prenylation, new and innovative strategies can be devised for the treatment of ALS. Thus, the following three
specific aims are proposed. In AIM 1, we will identify the prenyl transferase involved in motor axon pathology
by silencing these enzymes individually or in combination in Tg mSOD1 mice and then, we will compare, at
different time points, the number of lumbar and phrenic MNs and the NMJ innervation of ambulatory and
respiratory muscles that are critical to the quality of life and lifespan, respectively. We will also demonstrate the
generic nature of protein prenylation in ALS-related motor axon pathology by assessing the most effective
silencing identified above in a non-SOD1 model of ALS. In AIM 2, we will ascertain the specificity of protein
prenylation for motor axon pathology by monitoring behavioral, electrophysiological and anatomical parameters
in Tg mSOD1 mice deficient in the pro-cell death gene Bax with and without prenylation inhibition. Since Bax
deletion abrogates spinal MN death but not motor axon pathology in these mice, Tg mSOD1/Bax–/– animals will
enable us to determine whether: (i) motor axon pathology and MN death are governed by distinct molecular
programs and (ii) inhibition of both prenylation and Bax not only delays the onset of motor deficit but also
extends lifespan. In AIM 3, we will elucidate the specific prenylated proteins that contribute to motor axon
pathology by generating the MN prenylated proteome and then, use this information to perform a loss-of-
function screening in an in vitro model of ALS-like axon pathology. Lastly, those silenced MN prenylated
proteins that mitigate the axon phenotype in vitro will be validated in Tg mSOD1 mice using the same tests as
in AIM 2. In light of the above, we expect that the successful completion of the proposed work will identify the
prenylation pathway and its targets that contribute to motor axon pathology in ALS. These fin...

## Key facts

- **NIH application ID:** 10214709
- **Project number:** 5R01NS107442-04
- **Recipient organization:** COLUMBIA UNIVERSITY HEALTH SCIENCES
- **Principal Investigator:** SERGE E PRZEDBORSKI
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2021
- **Award amount:** $522,649
- **Award type:** 5
- **Project period:** 2018-09-01 → 2023-05-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10214709

## Citation

> US National Institutes of Health, RePORTER application 10214709, Mechanisms of Axon Pathology in ALS (5R01NS107442-04). Retrieved via AI Analytics 2026-05-23 from https://api.ai-analytics.org/grant/nih/10214709. Licensed CC0.

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