Role of Huntingtin-Associated Protein on Microtubule-Dependent Trafficking in Mice

Role of huntingtin-associated protein on microtubule-dependent trafficking in mice Neurodegenerative diseases comprise a heterogeneous group of neurological disorders characterized by a progressive, age-dependent decline in neuronal function and loss of selected neuronal populations. Alterations in intracellular trafficking and synaptic function, and eventually cell death represent critical pathogenic events in these diseases, but molecular mechanisms underlying these defects remain unclear. Huntington’s disease (HD) is a well established model for neurogeneration research due to its single causative gene mutation. The HD protein, huntingtin (Htt), and the first identified partner, Huntingtin-associated protein-1 (HAP1), are known to be involved in intracellular trafficking. Loss of HAP1 inhibits microtubule-dependent protein trafficking to and from synapses, and results in impairment of neurite integrity and extension in mouse brains. In a preliminary study, we found that HAP1 is required to control the physiological number of a set of neurons. Mounting evidence suggests a role of HAP1 in neuroprotection by transporting neurogenic molecules via microtubules. However, what molecules and cargos are associated with HAP1 has not been well studied. Therefore, we will precipitate microtubules from mouse brains either expressing or lacking HAP1, and analyze their composition using mass spectrometry. Molecular and biochemical techniques will be used to verify the findings, and reveal the detailed mechanism. We hope to provide more information of neurodegeneration and promote human health.