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.

Public Health Relevance

With the exception of head trauma, diseases of myelin are the major cause of permanent neurological disability in young adults. Myelin insulates nerve fibers and facilitates fast communication between nerve cells. Myelin also provides support that is essential for nerve fiber survival. Neurological disability in myelin disease results from nerve fiber death. This proposal investigates how nerve fibers die as a result of myelin disease. Our studies will identify new ways to treat diseases of myelin and reduce the progression of neurological disability in individuals with myelin disease.

Agency
National Institute of Health (NIH)
Institute
National Institute of Neurological Disorders and Stroke (NINDS)
Type
Unknown (R35)
Project #
1R35NS097303-01
Application #
9160948
Study Section
Special Emphasis Panel (ZNS1)
Program Officer
Utz, Ursula
Project Start
2016-12-01
Project End
2024-11-30
Budget Start
2016-12-01
Budget End
2017-11-30
Support Year
1
Fiscal Year
2017
Total Cost
Indirect Cost
Name
Cleveland Clinic Lerner
Department
Other Basic Sciences
Type
Schools of Medicine
DUNS #
135781701
City
Cleveland
State
OH
Country
United States
Zip Code
44195
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