Document text
Principal Investigator: Jie Jiang
Organization: EMORY UNIVERSITY
Fiscal Year: 2024
Award: $75,699
Funding agency: National Institute of Neurological Disorders and Stroke
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.
Terms: <ALS patients><Amyotrophic Lateral Sclerosis><Amyotrophic Lateral Sclerosis Motor Neuron Disease><Amyotrophic Lateral Sclerosis patients><Behavioral><Cell Body><Cells><Cessation of life><Clinical><Clinical Trials><Cramp><DNA Alteration><DNA Sequence Alteration><DNA mutation><Death><Degenerative Neurologic Disorders><Disease><Disorder><Dysfunction><Enhancers><Fasciculation><Functional disorder><Gehrig's Disease><Genetic><Genetic Alteration><Genetic Change><Genetic defect><Genetic mutation><Human><Intervention><Intervention Strategies><Lou Gehrig Disease><Mice><Mice Mammals><Modern Man><Molecular><Motor Cell><Motor Cortex><Motor Neurons><Murine><Mus><Muscle><Muscle Cramp><Muscle Tissue><Muscle Weakness><Muscle fasciculation><Muscular Cramp><Muscular Fasciculation><Muscular Weakness><Mutation><Nerve Cells><Nerve Unit><Nervous System Degenerative Diseases><Neural Cell><Neural Degenerative Diseases><Neural Fasciculation><Neural degenerative Disorders><Neurocyte><Neurodegenerative Diseases><Neurodegenerative Disorders><Neurologic Degenerative Conditions><Neurons><Palsy><Paralysed><Pathogenesis><Pathologic><Pathology><Pathway interactions><Patients><Physiopathology><Play><Plegia><Rodent Model><Role><SOD-1><SOD-1 protein><SOD1><SOD1 gene><SOD1 gene product><Sequence Alteration><Therapeutic Intervention><Transgenic Mice><Viral><degenerative diseases of motor and sensory neurons><degenerative neurological diseases><experience><genome mutation><genomic alteration><insight><intervention therapy><interventional strategy><motoneuron><muscular><nerve cell death><nerve cell loss><neural><neurodegenerative illness><neuron cell death><neuron cell loss><neuron death><neuron loss><neuronal><neuronal cell death><neuronal cell loss><neuronal death><neuronal loss><neurophysiological><neurophysiology><paralysis><paralytic><parent grant><pathophysiology><pathway><social role><superoxide dismutase 1><therapeutic target><tool>