# Mechanisms underlying the protective role of glycolysis in ALS

> **NIH NIH R21** · UNIVERSITY OF ARIZONA · 2020 · $420,113

## Abstract

ALS is a fatal neurodegenerative disease for which there is no cure. Elucidating the molecular mechanisms
underlying motor neuron dysfunction and death is imperative for devising successful therapeutic strategies. The
Zarnescu Lab has developed a Drosophila model of ALS based on TDP-43, which recapitulates several aspects
of disease including cytoplasmic aggregates, locomotor dysfunction and reduced lifespan. Using powerful
genetic and molecular tools we have identified novel targets and protein partners of TDP-43 that modulate its
toxicity in vivo. In collaboration with the Sattler Lab (Barrow Neurological Institute) we have validated our findings
from flies to patient derived motor neurons and spinal cords in what we call a “fly to man” approach. Using this
strategy, we have recently discovered that degenerating motor neurons upregulate glycolysis as a compensatory
mechanism. Interestingly, it has recently become clear, that contrary to what was previously thought about
metabolism in the CNS, neurons are capable of glycolysis and even assemble glycolytic enzymes at synapses
to handle the demands of rapid synaptic communication or to handle stress. We have found that
phosphofructokinase (PFK), the rate limiting enzyme in glycolysis is significantly upregulated in a fly model of
TDP-43 proteinopathy, patient derived iPSC motor neurons and spinal cords with TDP-43 pathology. Notably,
over-expression of PFK is sufficient to rescue, while knocking down PFK aggravates TDP-43 dependent
locomotor defects in motor neurons. Interestingly, it has been shown that PFK localizes to the neuromuscular
junction of C. elegans under hypoxic stress. The clustering of PFK promotes synaptic vesicle recycling thereby
maintaining synaptic function during times of high energy demand. Stressed yeast cells form glycolytic (G) bodies
that contain PFK as well as chaperones, VCP and translation elongation/termination factors. Our findings about
PFK in ALS and these recent reports about PFK suggest that in order to compensate for cellular energetics
deficits caused by mitochondrial dysfunction, degenerating motor neurons reroute ATP production onto
glycolysis to survive. We hypothesize that increased glycolysis may support the synaptic vesicle cycle
and/or improve mitochondrial function via synaptic G bodies. To test this hypothesis we will: 1) Determine
the mechanism by which PFK mitigates motor neuron dysfunction in ALS (i.e., improved synaptic vesicle cycle
and/or mitochondrial function); 2) Determine G body composition and dynamics at synapses under normal
conditions and in disease. Our “fly to man” approach enables us to first take advantage of powerful genetic tools
and accessibility of the neuromuscular junction in flies then validate key findings in patient derived motor neurons.
The results from these experiments will help formulate new hypotheses about neuronal metabolism and survival
in disease.

## Key facts

- **NIH application ID:** 10143639
- **Project number:** 1R21NS115514-01A1
- **Recipient organization:** UNIVERSITY OF ARIZONA
- **Principal Investigator:** DANIELA C ZARNESCU
- **Activity code:** R21 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2020
- **Award amount:** $420,113
- **Award type:** 1
- **Project period:** 2020-09-30 → 2022-05-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10143639

## Citation

> US National Institutes of Health, RePORTER application 10143639, Mechanisms underlying the protective role of glycolysis in ALS (1R21NS115514-01A1). Retrieved via AI Analytics 2026-07-20 from https://api.ai-analytics.org/grant/nih/10143639. Licensed CC0.

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