Amyotrophic lateral sclerosis (ALS) is a progressive, fatal disease characterized clinically and pathologically by progressive weakness and degeneration of motor neurons. A subset of patients can also have frontotemporal dementia with cortex injury. Though the symptoms of ALS are due to neuron degeneration, extensive research has shown that support cells in the CNS, including microglia, astrocytes, and recently oligodendrocytes, contribute to motor neuron degeneration. Our lab and others have shown that oligodendrocytes degenerate in ALS and that dysfunctional oligodendrocytes contribute to motor neuron degeneration, perhaps through failure of metabolic support to neurons. Oligodendrocyte dysfunction has been found in sporadic ALS, but also familial ALS associated with mutations in superoxide dismutase. Importantly, research from our laboratory has shown that oligodendrocytes play a critical role in neurodegeneration in SOD1 mice, since removing mutant SOD1 specifically from oligodendrocyte precursor cells (OPCs) and oligodendrocytes significantly prolongs lifespan in this mouse model of ALS. In the last several years, many research groups have focused on the recently discovered hexanucleotide repeat expansions (HREs) in C9orf72, which is the most common cause of familial ALS and also a common cause of frontotemporal dementia. These studies have determined that the neurotoxicity is likely due to both RNA- and dipeptide repeats (DPR) protein-mediated events. The exact mechanism by which these events produce toxicity is unknown, but published work by our laboratory and others has demonstrated that nucleocytoplasmic transport and nuclear pore proteins are disrupted in neurons expressing C9orf72HREs and restoration of this critical cell function leads to attenuation of neuronal toxicity. To date, there has been only one study on the role of C9orf72HREs in oligodendrocytes. In this proposal, we will thoroughly investigate the role of C9orf72HREs in OPCs and oligodendrocytes and their contribution to cellular dysfunction and degeneration in cellular and mouse models. We hypothesize that oligodendrocytes are dysfunctional in C9orf72 ALS and that alterations of nucleocytoplasmic transport lead to oligodendrocyte injury and reduced capacity for OPC differentiation. Specifically we propose to determine whether there is oligodendrocyte degeneration and OPC proliferation in ALS patients, and animal models with C9orf72 HREs. Our preliminary studies suggest C9orf72 is highly expressed in oligodendrocytes, which are dysfunctional in C9orf72 patients. We will then determine whether OPCs fail to differentiate and/or oligodendrocytes degenerate in C9orf72 ALS due to direct effect of repeat expansion on oligodendrocytes or an indirect effect from neuronal toxicity. Using oligodendrocyte monocultures and co-cultures with neurons derived from C9orf72 iPS cells and C9BAC mice, along with appropriate controls, we will evaluate OPC and oligodendrocyte proliferation, differentiation, survival, myelination, and support of neurons. We will also evaluate the impact on oligodendrocytes in vivo through viral vectors expressing HREs selectively in oligodendrocytes or neurons. To better understand the mechanism of oligodendroglial injury, we will determine whether OPCs or oligodendrocytes have dysfunctional nucleocytoplasmic transport in ALS patients and C9orf72HREs BAC transgenic mice. Finally, in hopes of using these model systems to mitigate injury, we will determine whether dysfunctional nucleocytoplasmic transport in OPCs and oligodendrocytes can be attenuated through genetic and pharmacologic techniques, including antisense oligonucleotides and nuclear transport modulators.

Public Health Relevance

RELEVANCE TO HUMAN HEALTH Understanding the pathophysiology and development of new therapeutics for ALS, ALS/FTD and FTD has been an enormous challenge. Recently the development of human disease induced pluripotent cell lines representing the natural disease in the most relevant cell types, motor neurons and glia, provides unprecedented tools to 1) study the underlying disease process, 2) allow for identification of disease markers of pathology and of drug actions and 3) provide critical tools for future drug discovery and drug action validation. Emerging data suggest that oligodendroglia may participate in the disease and understanding the injury to these cells may open opportunities for new approaches to ALS and dementia. Eventually these ALS/FTD model systems will also be useful to compare common and uncommon pathways between ALS and other neurodegenerative models.

National Institute of Health (NIH)
National Institute of Neurological Disorders and Stroke (NINDS)
Research Project (R01)
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Cellular and Molecular Biology of Glia Study Section (CMBG)
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Gubitz, Amelie
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Johns Hopkins University
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Eftekharzadeh, Bahareh; Daigle, J Gavin; Kapinos, Larisa E et al. (2018) Tau Protein Disrupts Nucleocytoplasmic Transport in Alzheimer's Disease. Neuron 99:925-940.e7
Zhang, Ke; Daigle, J Gavin; Cunningham, Kathleen M et al. (2018) Stress Granule Assembly Disrupts Nucleocytoplasmic Transport. Cell 173:958-971.e17
Philips, Thomas; Rothstein, Jeffrey D (2017) Oligodendroglia: metabolic supporters of neurons. J Clin Invest 127:3271-3280