The overall goal of this project is to delineate the mechanism of neuronal degeneration in Alzheimer's disease (AD) relevant to abnormalities of the ubiquitin (Ub)-proteasome system (UPS) leading to altered axonal transport and mitochondrial stress. Abnormalities of the UPS with accumulation of ubiquitinated protein aggregates, and mitochondrial dysfunction occur in AD and other age-related neurodegenerative diseases. However, the relationship between dysregulation of the UPS and mitochondrial stress remains poorly understood. We recently found that a mutant form of Ub, termed Ub+1, which was identified in human brain with AD and other tauopathies, accumulates in mitochondria and causes a trafficking jam in neuronal processes preceding neuritic destruction and cell death. Moreover, preliminary studies demonstrate abnormal mitochondria-associated accumulation of Ub species in neuronal cells exposed to beta-amyloid (Ab) or proteasome inhibitors. These findings indicate a potential link between UPS dysfunction, impaired axonal transport and mitochondrial stress. We therefore hypothesize that various Ub species, i.e., aberrant Ub and ubiquitinated protein aggregates, (1) are targeted to mitochondria and thereby (2) directly impair the axonal transport and function of mitochondria in neurons leading to neuronal cell death in AD. We propose to use neuron cultures, cell free system analyses, transgenic mice and human postmortem tissues to test these hypotheses with the following Specific Aims: 1. determine whether aberrant ubiquitin or excessive ubiquitinated proteins directly target to mitochondria in neurons; 2. determine whether abnormal ubiquitin species interfere with neuritic transport and function of mitochondria in neurons; 3. determine the relationship between abnormal Ub species, mitochondrial stress and neurodegeneration in vivo. Elucidation of the molecular basis of the adverse effects of UPS-mitochondria interactions may contribute to the development of novel pharmacological approaches to treat AD
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| Tan, Zhiqun; Shi, Lei; Schreiber, Steven S (2009) Differential Expression of Redox Factor-1 Associated with Beta-Amyloid-Mediated Neurotoxicity. Open Neurosci J 3:26-34 |
| Yang, Zhikuan; Zhang, Qingjiong; Ge, Jian et al. (2008) Protective effects of tetramethylpyrazine on rat retinal cell cultures. Neurochem Int 52:1176-87 |
| Tan, Z; Sun, X; Hou, F-S et al. (2007) Mutant ubiquitin found in Alzheimer's disease causes neuritic beading of mitochondria in association with neuronal degeneration. Cell Death Differ 14:1721-32 |
