Grant: Project Grant

Brain diseases characterized by age-related progressive loss of neural tissue (neurodegeneration), like Alzheimer and Parkinson disease, often start with abnormal connectivity between brain cells and regions. Huntington disease (HD) is an inherited brain disorder with average onset in middle age and progressive impairment of movement, cognition and mood. Neurodegeneration is most severe in two regions -- the cortex and striatum, and the first changes occur at connections (synapses) between these regions. Despite a Phase 3 trial using a genetic approach to reduce the mutated protein in HD patients (NCT03761849), evidence suggests changes in synapses may not be reversed once the disease has started. Moreover, there are significant challenges for scaling up therapeutic delivery of this biological agent via regular lumbar punctures over many years in the HD patient population. There is a critical need to develop complementary therapies to normalize function of brain connections before clinical disease onset, by investigating the cellular mechanisms underlying those changes. We propose to test the role of cellular calcium regulation - crucial for the health and signaling properties of brain cells - in triggering altered synapse function between cortex and striatum. We focus on two major mechanisms: the cellular calcium storage and release compartment called the endoplasmic reticulum, and the NMDA receptor, a protein complex that receives and transmits signals by the brain chemical glutamate. We will use a variety of techniques, tools and drugs to investigate the contribution of these mechanisms to synaptic dysfunction in models of HD. We will then conduct preclinical trials to test drugs targeting these mechanisms for effectiveness in restoring coordinated movement, skilled learning and cortex-striatum connectivity. Our results will guide development of therapies to preserve brain connections critical for maintaining normal function longer in HD gene mutation carriers.