The prevalence of neurodegenerative disorders is increasing due to aging population. New intervention strategies and monitoring biomarkers are required. Neurodegenerative disorders are characterized by progressive neuropsychiatric dysfunction and loss of specific subtypes of neuron. Mounting evidence showed that mutations of proteins involved in microtubule-dependent trafficking may induce these neuronal pathologies through dysfunction of calcium homeostasis. The first identified HD protein (Htt) partner, Htt-associated protein-1 (Hap1), was found to be essential for animal survival. Hap1 associates with microtubule-dependent motor proteins, and involved in the transport of various proteins such as AD-related amyloid precursor protein (APP) and membrane receptors such as calcium-mediating inositol triphosphate receptor (IP3R). Our recent study revealed that Hap1 was important for the maintenance of a specific neuron population in mice. However, MTT assay and flow cytometric analysis demonstrated inhibition of cell proliferation by Hap1 overexpression. It is consistent with previous finding that Hap1 promotes neuron differentiation and survival. A proteomic analysis revealed that there were many regulators of neuronal activities reduced association with microtubules in Hap1-defecient mouse brain. These proteins include a couple of calcium-binding proteins such as parvalbumin (Pva) and breakpoint cluster region protein (Bcr) which is also a regulator of Rho GTPases. Furthermore Bcr was colocalized with Hap1 in neuronal cells in our immunocytochemistry study, suggesting that Hap1 may participate in calcium trafficking by regulating the activity of these neuron-favorite proteins. In this research proposal, we would first like to further investigate the relationships between Hap1 and these calcium-regulating proteins. Second, we will determine the changes of those Hap1-related proteins in the brain and body fluids of our Hap1-null animal. Finally, AD patients’ sera may be analyzed for the existence and changes of Hap1-regulated proteins or biomarkers. We will keep investigating the relationships of Hap1 and its partners, and discover the targets for diagnosis and treatment of certain neurodegenerative diseases.
|Effective start/end date||8/1/13 → 7/31/14|
- Alzheimer’s disease
- Huntingtin-associated protein
- breakpoint cluster region protein