Alzheimer's disease (AD) is the leading cause of dementia in the elderly, characterized by neurofibrillary tangles, senile plaques and a progressive loss of neuronal cells in selective brain regions. Mitochondrial dysfunction is a prominent and early feature of the disease, although the underlying mechanism is still not clear. Mitochondria are dynamics organelles that undergo continual fission and fusion events which serve crucial physiological function. Our recent studies demonstrated that an altered balance in mitochondrial fission and fusion was likely an important mechanism leading to mitochondrial and synaptic/neuronal dysfunction in AD brain. Mutations in presenilins (PS) cause early-onset familial form of AD (FAD). PS1 is found in mitochondria and mutant PS1 affects mitochondrial function and transport. Our preliminary studies revealed that PS1 knockout (KO) primary neurons demonstrated significant changes in mitochondria morphology, distribution and movement which could be prevented by co-expression of wild-type PS1, but not FAD-causing PS1 mutant, suggesting that presenilins are involved in the regulation of mitochondrial dynamics which may be impaired by PS1 FAD mutations. Most importantly we found that PS1 physically interacted with DLP1, a key regulator of both mitochondrial fission and distribution. These studies suggest that a detailed investigation into the potential role of PS1 in mitochondrial function and dynamics is warranted. Based on our preliminary studies, we hypothesize that FAD-associated PS1 mutants cause impaired regulation of mitochondrial dynamics through specific interaction with DLP1 which causes mitochondrial dysfunction and redistribution which adversely affects neuronal functions including causing synaptic abnormalities in AD. To begin to address this hypothesis, the following specific aims will be pursued: 1) to determine the effect of FAD-associated PS1 mutants on mitochondria dynamics;2) to determine whether PS1-DLP1 interaction mediates the effects of FAD-associated PS1 mutants on mitochondrial dynamics.
Mutations in presenilin genes cause familial Alzheimer's disease (FAD). Although mitochondrial dysfunction is a prominent feature in PS1-associated FAD, how PS1 mutants may lead to mitochondrial dysfunction and neurodegeneration remains elusive. We propose to investigate whether PS1 is specifically involved in the regulation of mitochondrial dynamics and PS1 mutants cause mitochondrial abnormalities by impairing mitochondrial dynamics. The completion of this project will provide new insights about the pathogenesis of AD and may lead to novel therapeutic targets for AD.
|Wang, Wenzhang; Wang, Luwen; Lu, Junjie et al. (2016) The inhibition of TDP-43 mitochondrial localization blocks its neuronal toxicity. Nat Med 22:869-78|
|Wang, Wenzhang; Zhang, Fan; Li, Li et al. (2015) MFN2 couples glutamate excitotoxicity and mitochondrial dysfunction in motor neurons. J Biol Chem 290:168-82|
|Bonda, David J; Wang, Xinglong; Lee, Hyoung-Gon et al. (2014) Neuronal failure in Alzheimer's disease: a view through the oxidative stress looking-glass. Neurosci Bull 30:243-52|
|Hwang, Ran-Der; Wiemerslage, Lyle; LaBreck, Christopher J et al. (2014) The neuroprotective effect of human uncoupling protein 2 (hUCP2) requires cAMP-dependent protein kinase in a toxin model of Parkinson's disease. Neurobiol Dis 69:180-91|
|Li, Li; Wang, Wenzhang; Welford, Scott et al. (2014) Ionizing radiation causes increased tau phosphorylation in primary neurons. J Neurochem 131:86-93|
|Wang, Xinglong; Wang, Wenzhang; Li, Li et al. (2014) Oxidative stress and mitochondrial dysfunction in Alzheimer's disease. Biochim Biophys Acta 1842:1240-7|
|Yan, Michael H; Wang, Xinglong; Zhu, Xiongwei (2013) Mitochondrial defects and oxidative stress in Alzheimer disease and Parkinson disease. Free Radic Biol Med 62:90-101|
|Wang, Wenzhang; Li, Li; Lin, Wen-Lang et al. (2013) The ALS disease-associated mutant TDP-43 impairs mitochondrial dynamics and function in motor neurons. Hum Mol Genet 22:4706-19|
|Zhu, Xiongwei; Perry, George; Smith, Mark A et al. (2013) Abnormal mitochondrial dynamics in the pathogenesis of Alzheimer's disease. J Alzheimers Dis 33 Suppl 1:S253-62|