Identification of Potential Markers in Huntingtin Associated Protein-Related Nervous Diseases

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 gene regulation and intracellular trafficking, and eventually cell death represent critical pathogenic events in these diseases; however, molecular mechanisms underlying these defects remain unclear. Huntington’s disease (HD) is a well established research model for neural degeneration and pathology because all HD patients have mutations on the same causative gene. 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 trafficking in neurons, and results in impairment of neurite integrity and extension in mouse brains. Most of the known HAP1-interacting partners are also trafficking proteins, and their mutations also cause nervous diseases. Our recent study showed that HAP1 is required for controlling the physiological number of a subset 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 precipitated microtubules from mouse brains either expressing or lacking HAP1, and analyze their composition using mass spectrometry. In the preliminary data, we found nearly 30 proteins largely reduced association with microtubule in HAP1 deficiency. Indeed, a group of proteins known as regulators of cell proliferation are in this category. Most of the others in the same category are known to be involved in intracellular trafficking, small GTPase regulation and calcium signaling. Molecular and biochemical techniques will be used to verify the findings, and reveal the detailed mechanism that may lead us to the discovery of potential biomarkers in nervous diseases. We hope to provide more information on neuronal physiology and pathology, and promote human health.