Amyotrophic lateral sclerosis (ALS) is a debilitating neurodegenerative disorder characterized by loss of motor neurons in the brain and spinal cord, and death from failure of respiratory muscles 3-5 years after diagnosis. The only FDA approved drug for ALS, Riluzole, is only marginally effective. A key to developing effective therapies is to understand why the disease affects only motor neurons. We hypothesize that understanding distinct expression profiles of motor neurons will inform their selective vulnerability to ALS, enabling the development of novel biomarkers and therapeutics for both sporadic and genetically inherited ALS, frontotemporal dementia (FTD)-associated ALS, and other motor neuron diseases. During the prior award period, we developed a powerful approach to studying microRNAs (miRNAs), which are key regulators of physiological and pathological processes, and generated the first ever profile of miRNAs enriched in motor neurons in ALS rodent and human spinal cord. Consistent with our hypothesis that a motor neuron-enriched miRNA profile would inform motor neuron disease mechanisms, we defined a pharmacoresponsive miRNA biomarker in ALS that reports on motor neuron loss and dysfunction in animal models. We propose to further develop this biomarker by elucidating the impact of miRNA release on ALS disease progression through non-cell autonomous mechanisms, assessing miRNA release from motor neurons and presence in CSF during disease in ALS models and human patients, and determining whether miRNAs define susceptibility of specific motor neuron pools, as not all motor neurons are equally susceptible to degeneration in ALS and ALS-FTD. With our lab's prior experience with motor neuron degeneration models and miRNAs, strong local collaborations for bioinformatics, outstanding neurodegenerative disease colleagues, and PI's record of successful translation of therapeutics into humans, our team is uniquely positioned to carry out these studies. Our motor neuron specific miRNA approach has a high likelihood of providing insight into the mechanisms underlying motor neuron degeneration and may also be the foundation for a novel therapy for ALS, FTD, and other motor neuron diseases.
miRNAs are key regulators of cellular processes and have been studied as clinically useful biomarkers, governors of disease progression, and robust therapeutic targets in a wide array of diseases. Our study will investigate miRNAs that are enriched in motor neurons, the main cellular population affected in amyotrophic lateral sclerosis (ALS), in order to determine whether these motor neuron-enriched miRNAs could serve as novel therapeutic targets and to further understand how miRNAs may contribute to disease progression in ALS patients.
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