# Sphingosine-1-phosphate system as a therapeutic target for amyotrophic lateral sclerosis

> **NIH VA I01** · VA BOSTON HEALTH CARE SYSTEM · 2021 · —

## Abstract

Amyotrophic lateral sclerosis (ALS) is a progressive, fatal, and untreatable neurological disease characterized
by muscle weakness, atrophy and spasticity, typically leading to paralysis and death within 3-5 years after
symptom onset. Pathologically, ALS is primarily characterized by the degeneration and death of motor neurons
(MN) in the cerebral cortex and spinal cord. Damage to MN is associated with the onset of ALS however the
progressive loss of motor neurons is a non-cell autonomous process that requires damage of neighboring non-
neuronal cells. Indeed, the presence of reactive astrocytes and microglia in heavily-affected areas is a hallmark
of ALS. Deregulation of lipid metabolism and malfunction of the immune system have been implicated in the
pathogenesis of ALS. Sphingolipid metabolism was identified as the most dysregulated pathway, and ceramide
species, which promote apoptosis and inflammation, were found to accumulate in postmortem spinal cord
samples of ALS patients. Influx of T lymphocytes into the central nervous system occur early in the disease.
While some lymphocytes activate neuroinflammation others, regulatory T cells (Tregs), hold neuroinflammation
in check. Protective and harmful phenotypes of microglia and astrocytes appear to coexist in affected tissue.
The fact that immunosuppressant treatments have been disappointing in ALS may be because of the dual nature
of the immune system. Fingolimod is a structural analog of sphingosine that has been approved for the oral
treatment of multiple sclerosis. Unlike conventional immunosuppressive drugs, fingolimod does not inhibit
lymphocyte activation but reduces the migration of pathogenic lymphocytes into the central nervous system
(CNS) and increases the number of circulating Tregs. Fingolimod readily crosses the blood brain barrier and in
the CNS, promotes the neuroprotective phenotype in glial cells. In a recent preclinical study, fingolimod improved
the survival rate of SOD1-G93A mice, a mouse model of ALS, and the beneficial effect was associated with
modulation of microglial activation and innate immunity. We propose a study to test the hypothesize that altered
the S1P signaling drives the proinflammatory activation of astrocytes and microglia in ALS and that treatment
with S1P modulators will interfere with the proinflammatory process to slow down (or recover) the degeneration
of MN with the ultimate goal of paving the way to find new therapies to treat or cure the disease. In Aim 1 we will
use two different mouse models of ALS (SOD1-G93A and TDP43-Q331K) and human postmortem lumbar cord
samples from ALS patients to investigate the S1P system in the etiology ALS to establish the rational for using
modulators of the S1P signaling system for the treatment of ALS. In Aim 2 we will perform a dose-response
study (1, 0.3, 0.1, and 0.03 mg/kg/day) starting at a pre- or post-onset stage using fingolimod that acts on
S1P1,3,4,5 and AUY954, a second generation S1P modulators with spe...

## Key facts

- **NIH application ID:** 10011983
- **Project number:** 1I01BX005180-01
- **Recipient organization:** VA BOSTON HEALTH CARE SYSTEM
- **Principal Investigator:** ALPASLAN DEDEOGLU
- **Activity code:** I01 (R01, R21, SBIR, etc.)
- **Funding institute:** VA
- **Fiscal year:** 2021
- **Award amount:** —
- **Award type:** 1
- **Project period:** 2021-07-01 → 2025-06-30

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10011983

## Citation

> US National Institutes of Health, RePORTER application 10011983, Sphingosine-1-phosphate system as a therapeutic target for amyotrophic lateral sclerosis (1I01BX005180-01). Retrieved via AI Analytics 2026-05-23 from https://api.ai-analytics.org/grant/nih/10011983. Licensed CC0.

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