Physiological and Genetic Analysis of Calhm1 function in C. elegans

University Of Pennsylvania, Philadelphia PA

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Abstract

DESCRIPTION (provided by applicant): Ion channel regulation of cell calcium plays critical roles in excitable cell signaling and neurodegenerative diseases. Recently, we demonstrated that the human Calhm1 gene encodes for a novel calcium-permeable ion channel and that a human polymorphism in Calhm1 may be linked to late-onset Alzheimer's disease. While these findings point to a potential role for mutant Calhm1 in disease, the physiological function(s) of Calhm1 is unknown. C. elegans expresses a single Calhm1 homolog, clhm-1. Heterologously expressed clhm-1 gives rise to currents with characteristics similar to human Calhm1. Like human Calhm-1, worm clhm-1 is expressed in excitable cells. Based on these data, we hypothesize that the physiological function(s) of Calhm is evolutionarily conserved from worms to humans. To define these functions, we will pursue two aims. First, we will analyze the biophysical properties of C. elegans clhm-1 to determine conserved aspects of Calhm channel function, using both heterologous expression and primary C. elegans cell cultures. Second, we will investigate the functional roles of clhm-1 in live worms, using both clhm-1 knockout strains and clhm-1 overexpression strategies. Our studies will provide the first detailed study of Calhm function in vivo and will offer crucial insights into this new ion channel family. PUBLIC HEALTH RELEVANCE: Proper regulation of cellular calcium levels is essential for cellular function, and derangements in such regulation are associated with numerous human neurodegenerative diseases. We discovered that a new calcium ion channel, called Calhm1, regulates cellular calcium levels and a human Calhm1 mutation accelerates the pathology of Late-onset Alzheimer's disease. Beyond these observations, the cellular function(s) of Calhm1 are unknown. Our proposed studies will investigate Calhm1 function in the model system C. elegans and will provide deeper insights into how this new protein may contribute to human disease.