Amyotrophic lateral sclerosis (ALS) is a progressive, fatal neurodegenerative disease that ends with degeneration in both upper and lower motoneurons. Approximately 10-15% of the diagnosed ALS cases are inherited, (familiar ALS) (FALS), while the remaining are sporadic. Clinically, the disease is characterized by muscle weakness, atrophy and fasciculations in the limbs and difficulty in swallowing and chewing. Patients typically die within 3-5 years of diagnosis due to respiratory failure. The long-term goals of this research are to determine the cellular mechanisms that lead to the progressive loss of motoneuronal function and pathogenesis of ALS, and to establish targets that can be used to develop a multifaceted therapeutic approach to delaying the progression of the degeneration. Our immediate goal, using a mouse model of ALS (SOD1 mice) and electrophysiological, as well as mitochondrial and calcium imaging methods, is to test our working hypothesis that presymptomatic alterations of intrinsic voltage-gated calcium and/or potassium channels in trigeminal motoneurons and presynaptic trigeminal proprioceptive primary afferent neurons occur simultaneously, and contribute to the hyperexcitability previously observed in SOD1 mutant mice. This information is important because simultaneous changes in intrinsic ion channel function in pre- and postsynaptic target neurons could 1) be complex conjoint signals to initiate the disease process, and 2) produce an increase in pre- or postsynaptic membrane excitability that leads to the observed spasticity and fasciculations observed in ALS patients, as well as 3) trigger the processes that lead to calcium excitotoxicity in vulnerable target neurons (trigeminal). Parallel studies on ALS resistant abducens motoneurons will provide valuable information on the mechanism(s) responsible for the differential vulnerability of motoneurons to the disease process. Our experiments will use a unique brainstem slice preparation that contains in close proximity, trigeminal and abducens motoneurons, as well as sensory Mes V neuronal cell bodies. Direct comparisons of changes in potassium and calcium channel properties, calcium concentration changes and assessment of mitochondrial function between different neuron types in control and SOD1 mutant animals will be obtained and provide valuable information on the pathogenesis of the ALS.

Public Health Relevance

Amyotrophic lateral sclerosis (ALS) is a fatal neuro-degenerative disease clinically characterized by progressive loss of muscle force and difficulty in swallowing and chewing, for which there is no cure. Neuronal ion channels produce the electrical signals necessary for proper sensory-motor function and abnormalities in these channels can lead to a variety of disorders. Detection of presymptomatic changes in ion channel function using animal models for ALS could lead to identification of physiological targets that can be used in development of therapeutic strategies to prolong life of those with ALS.

National Institute of Health (NIH)
National Institute of Neurological Disorders and Stroke (NINDS)
Exploratory/Developmental Grants (R21)
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Clinical Neuroplasticity and Neurotransmitters Study Section (CNNT)
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Gubitz, Amelie
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University of California Los Angeles
Schools of Arts and Sciences
Los Angeles
United States
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