# Pathogenesis of Neurological Disability in Primary Diseases of Myelin

> **NIH NIH R35** · CLEVELAND CLINIC LERNER COM-CWRU · 2021 · $871,750

## Abstract

ABSTRACT
Acquired and inherited diseases of myelin are the major cause of non-traumatic neurological
disability in young adults in the USA. Studies have also described myelin pathology in brains
from individuals with amyotrophic lateral sclerosis (ALS) and Alzheimer's disease (AD), and
myelin protein gene alleles are risk factors for schizophrenia, depression, and autism. In
addition to its insulating properties, therefore, myelin has multiple effects on neuronal function. It
is now accepted that axonal and neuronal degeneration cause permanent neurological disability
in individuals with primary myelin disease. My laboratory played a significant role in identifying
axonal and neuronal degeneration in brains from individuals with multiple sclerosis (MS), an
inflammatory demyelinating disease of the human central nervous system (CNS). We leveraged
these data to develop animal models that recapitulate mechanistic aspects of myelin-induced
axonal and neuronal degeneration. The purpose of the present proposal is to consolidate three
NINDS R01s that investigate mechanisms of myelin-induced neurodegeneration. We will
address three key questions. 1) How does myelin provide trophic support to axons? We
propose that transfer of ATP substrates is the major mechanism by which myelin provides
trophic support to axons. Disruption of this metabolic coupling in inherited myelin diseases
induces mitochondrial pathology/degeneration in paranodal axoplasm, which causes axonal
degeneration. 2) How does demyelination affect neurons and their synaptic connections? We
propose that demyelination alters neuronal gene expression, modulates dendritic structure, and
reduces neuronal viability; we further propose that remyelination will reverse these changes. 3)
How does subpial cortical demyelination occur? We propose that subpial demyelination occurs
by mechanisms that differ from immune-mediated mechanisms that demyelinate white matter
and that novel therapies are needed to prevent subpial demyelination. The biggest challenge
facing the myelin research community is the development of neuroprotective therapies. R35
funding will consolidate our efforts to identify new therapeutic targets that cause axonal and
neuronal degeneration in myelin diseases. This is essential for the development of
neuroprotective therapies that delay and possibly reverse permanent neurological disability in
individuals with myelin disease.

## Key facts

- **NIH application ID:** 10066371
- **Project number:** 5R35NS097303-05
- **Recipient organization:** CLEVELAND CLINIC LERNER COM-CWRU
- **Principal Investigator:** BRUCE D TRAPP
- **Activity code:** R35 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2021
- **Award amount:** $871,750
- **Award type:** 5
- **Project period:** 2016-12-01 → 2024-11-30

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10066371

## Citation

> US National Institutes of Health, RePORTER application 10066371, Pathogenesis of Neurological Disability in Primary Diseases of Myelin (5R35NS097303-05). Retrieved via AI Analytics 2026-05-23 from https://api.ai-analytics.org/grant/nih/10066371. Licensed CC0.

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