# Compromised LDH activity causes motor deficits and hastens ALS progression

> **NIH NIH R56** · WASHINGTON UNIVERSITY · 2022 · $503,248

## Abstract

Project Abstract
 Motor axon loss is a cardinal symptom of Motor Neuron Diseases including amyotrophic lateral sclerosis
(ALS). Schwann cells (SCs) myelinate and provide trophic support to axons in the peripheral nervous system
(PNS) and disruption of SC metabolism leads to demyelination and axon degeneration, both symptoms of
peripheral neuropathy. The lactate shuttle hypothesis proposes that glycolytic glial support cells supply lactate
to axons to sustain their high metabolic demands, a process that requires interconversion of lactate and pyruvate
via lactate dehydrogenase (LDH) in both glia and neurons. To test this hypothesis in the PNS, we deleted LDH
subunits LDHA and LDHB specifically in motor neurons (MNs), sensory neurons (SNs), or SCs. We find that
LDH deletion in SCs or MNs leads to progressive degeneration of motor axons, whereas LDH loss in SNs causes
no abnormalities in the sensory axons. These results support a model in which lactate shuttling from SCs
selectively sustains motor but not sensory axons and suggest that LDH activity and lactate shuttling play a role
in motor-dominated neuropathies such as ALS. Indeed, LDHB-deficient mice develop progressive motor
dysfunction similar to ALS mouse models, and LDH deficiency synergizes with a slowly progressing ALS model
to induce severe disease. In conjunction with these studies, we identified rare loss-of-function LDHB mutations
in ALS patients that are not present in controls.
 In this proposal, we outline experiments to examine the differential responses of MN and SN neurons to
loss of LDH function to identify pathways involved in the selective motor axon degeneration. We will use a cellular
complementation assay utilizing iPSC-derived neurons to dissect components involved in support of peripheral
motor axons. We will use biochemical and cellular complementation assays to examine LDHB variants found in
ALS patients and controls to determine if deleterious variants are enriched in ALS. We will study mice lacking
specific LDH isoforms in defined cell types to determine the cells involved in motor axon metabolic support and
the pathways they invoke to influence axon health. Additionally, we will use these LDH mutant mice to interrogate
how compromised lactate/pyruvate metabolism interacts with other ALS risk factors to speed disease
progression. Results of these studies will establish the relationship between LDH, lactate/pyruvate metabolism
in the PNS, and development of Motor Neuron Diseases including ALS, and stimulate development of new axo-
protective therapeutics for these devastating disorders.

## Key facts

- **NIH application ID:** 10647175
- **Project number:** 2R56AG013730-22
- **Recipient organization:** WASHINGTON UNIVERSITY
- **Principal Investigator:** JEFFREY D MILBRANDT
- **Activity code:** R56 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2022
- **Award amount:** $503,248
- **Award type:** 2
- **Project period:** 1996-07-01 → 2023-04-30

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10647175

## Citation

> US National Institutes of Health, RePORTER application 10647175, Compromised LDH activity causes motor deficits and hastens ALS progression (2R56AG013730-22). Retrieved via AI Analytics 2026-05-23 from https://api.ai-analytics.org/grant/nih/10647175. Licensed CC0.

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