# NAD+ metabolism and signaling in ALS models

> **NIH NIH R01** · UNIVERSITY OF WISCONSIN-MADISON · 2020 · $361,339

## Abstract

The long-term goal of the proposal is to develop new therapeutic strategies using mechanistic insights
drawn from understanding astrocyte-motor neuron interaction in amyotrophic lateral sclerosis (ALS). In
particular, the primary objective of this proposal is to better delineate the mechanisms responsible for the
protection conferred by enhancing nicotinamide adenine dinucleotide (NAD+) availability in ALS models. ALS
or Lou Gehrig's disease accounts for about 1 in 500 to 1 in 1,000 adult deaths in the United States and is
caused by the progressive degeneration of motor neurons in the spinal cord, brain stem, and motor cortex.
Motor neuron death leads to muscle weakness and paralysis causing death in one to five years from the time
of symptoms onset. Most ALS cases are sporadic (SALS) and exposure to yet unidentified environmental
toxicants might be responsible for SALS. About 5-10% of the cases are inherited (familial ALS, FALS) but
FALS and SALS are phenotypically indistinguishable, and a significant share of our understanding come from
the study of rodent models over-expressing ALS-linked mutant human superoxide dismutase 1 (hSOD1).
Several lines of evidence underscored the contribution of non-neuronal cells in the neurodegenerative process
and astrocytes appear to have a decisive role in the progression of the disease. Accordingly, primary
astrocytes isolated from mutant hSOD1 over-expressing mice induce motor neuron death in co-culture, and it
has been demonstrated that astrocytes differentiated from spinal cord autopsy-derived neuronal progenitor
cells from FALS and SALS patients are also toxic for motor neurons in co-culture. We have shown that over-expression of the NAD+-synthesizing enzyme, NAMPT, or increasing the activity of two sirtuins (SIRT3 and/or
SIRT6) is protective in a co-culture model of ALS. Sirtuins are a family of enzymes capable of catalyzing NAD+-dependent deacylation and mono(ADPribosyl)ation reactions, and play a key role in transcription, DNA repair,
metabolism, and oxidative stress resistance. Our previously published data and ongoing experiments
demonstrate that modulating NAD+ metabolism and signaling is protective in a co-culture model of ALS, while
the expression of enzymes involved in NAD+ synthesis and NAD+-dependent signaling is altered in ALS
patients. Moreover, enhancing NAD+ levels by dietary supplementation with a metabolic precursor
(nicotinamide riboside) exerts neuroprotective effects in an ALS mouse model. Thus, we seek to better define
the role of NAD+-dependent signaling during motor neuron degeneration. The results obtained during the
previous funding period rationally support the development of cell-type specific approaches to better target
NAD+ metabolism and signaling in ALS. Since we have shown that therapeutic targets identified in our
astrocyte-motor neuron co-culture system have a beneficial effect when translated into animal models of ALS,
the proposal is likely to provide a mechanistic insig...

## Key facts

- **NIH application ID:** 10051683
- **Project number:** 2R01NS089640-07
- **Recipient organization:** UNIVERSITY OF WISCONSIN-MADISON
- **Principal Investigator:** Marcelo R Vargas
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2020
- **Award amount:** $361,339
- **Award type:** 2
- **Project period:** 2020-09-30 → 2025-08-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10051683

## Citation

> US National Institutes of Health, RePORTER application 10051683, NAD+ metabolism and signaling in ALS models (2R01NS089640-07). Retrieved via AI Analytics 2026-05-23 from https://api.ai-analytics.org/grant/nih/10051683. Licensed CC0.

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