Role of ADAM10 in Huntington’s Disease

Huntington’s Disease (HD) is an inherited brain disorder. The HD gene is known and we all possess it in its normal version. A genetic defect in the HD gene causes HD, which typically begins in mid-life, between the ages of 30 and 40, and it is progressive and fatal after 16-20 years. Symptoms include uncontrolled movements, cognitive and behavioral impairments. Dysfunction of synaptic circuitries is a hallmark of HD pathogenesis and strategies aimed at normalizing this dysfunction in HD are needed. This proposal is focused on the role of ADAM10 in HD. ADAM10 is a protein endowed with enzymatic activity that is critical in the brain for its role in synaptic structure and function. Our recent data indicate that normal huntingtin regulates ADAM10 activity both in the developing and adult brain. When huntingtin bears the genetic defects causing HD, ADAM10 activity is impaired. Therefore, ADAM10 represents a new interesting molecule to be investigated in HD in which one of the main pathological mechanisms is represented by dysfunction of brain circuitries. With this proposal we will test whether impairment in ADAM10 activity contributes to the alteration of the structure and function of synaptic circuitries in HD. Moreover, we will employ strategies aimed at normalizing ADAM10 activity in the brain to test whether this will improve brain circuitries and performance of HD mice. Confirmation that ADAM10 is affected in the HD brain and that manipulating its activity normalizes synaptic circuitry and is beneficial to HD mice will support the development of new therapeutic strategies for HD.