Wednesday, January 15, 2025
1/15/2025
PROJECT SUMMARY/ABSTRACT Amyotrophic lateral sclerosis (ALS) is a devastating neurodegenerative disease caused by the loss of upper and lower motor neurons, leading to progressive muscle weakness and paralysis. Many altered molecular and cellular pathways have been implicated in disease pathogenesis. However, determining which are causative remains challenging, and many clinical trials have failed in the last few decades. One explanation for the unsuccessful clinical interventions is the difficulty of rescuing dying motor neurons once death has been triggered, meaning that therapeutic interventions must be implemented early in the disease. Months before clinical onset, ALS patients often experience fasciculations and cramps (i.e., spontaneous and persistent muscle twitching), suggesting increased neural activity and excitability. Indeed, neurophysiological studies in patients and rodent models with ALS-associated genetic mutations have identified that circuit dysfunction, specifically motor cortex hyperexcitability, are among the earliest pathologies. Recently, two studies suggested that upper corticospinal motor neurons (CSMN) in the motor cortex play an essential role in the low motor neuron death of transgenic mice expressing human SOD1 mutations. We thus hypothesize that CSMN hyperexcitability might drive ALS pathogenesis. We propose to utilize recently developed enhancer-driven viral tools that allow cell-specific targeting to 1) perform cutting-edge chemogenetics to modulate neuronal activity to determine whether dampening CSMN hyperexcitability in the late pre-symptomatic stage can mitigate ALS- related behavioral and pathological deficits in SOD1G93A mice, and 2) identify cell-specific altered molecular pathways leading to motor cortex hyperexcitability. This study has significant implications in developing therapeutics targeting this early clinical abnormality in ALS patients.
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