Huntingtin-Associated Protein-Mediated Vesicular Trafficking Biomarkers in Neurodegenerative Diseases

The era of aged population with continuing pollution is accompanied by increasing patients with neurodegenerative disorders such as Alzheimer’s disease (AD). The development of new diagnostic biomarkers becomes urgent. In this research project, we hope to find out reliable biomarkers which correlate with early pathogenesis. Mounting evidence showed that mutations of proteins involved in microtubule-dependent trafficking induce these neuronal pathologies. The microtubule-dependent vesicular trafficking of AD-related amyloid precursor protein (APP) and tropomyosin receptor kinases (TRKs) involves huntingtin (Htt) and its associated proteins in neurons. These proteins include Htt-associated protein (HAP)-1, Abelson helper integration site-1 (AHI1 or Jouberin) and microtubule-dependent motor proteins, for example, kinesin light chain (KLC)-2. Recently we analyzed human blood and found a significant reduction of Htt, AHI1 and KLC2 in AD patients. The results were consistent with an impairment of vesicular trafficking in the patients. We will compare the levels of these proteins and their post-translational modification statuses in the blood of AD to those in the patients with different neurodegenerative disorders such as mild cognitive impairment (MCI), stroke and vascular dementia. Then the sensitivity and specificity of these biomarkers in diagnosing different neurodegenerative diseases can be defined. An HAP1-dependent microtubule proteomic analysis has been done using HAP1-KO mouse brains. More candidate biomarkers were suggested. Their relationships with the known vesicular trafficking proteins will be determined using mouse brains and model cells. To get insights of AD pathological mechanism, we are establishing a cell line adopting the genetics in a subset of AD patients. The levels and statuses of these vesicle-related proteins in the model cells will be checked and then manipulated to interfere with the pathogenic process.