Our laboratory has shown that systemic inhibition of mitochondrial complex I with rotenone reproduces in rats and monkeys many features of PD, including dopaminergic degeneration, Lewy body and neurite (alpha-synuclein) pathology, DJ-i modification and translocation to mitochondria, and impairment of the ubiquitin-proteasome system. Most recently, we have found that there is iron deposition in substantia nigra of rotenone treated rats and monkeys, which appears identical to that seen in PD brains. In this model, transferrin (Tf) becomes oxidized (at Cys26o) and accumulates in nigral dopaminergic neurons. In collaboration with Charleen Chu, director of the Neuropathology Core, Greenamyre has found a similar - previously undescribed - accumulation of transferrin in nigral neurons in human postmortem specimens from PD cases. Additionally, he has found that transferrin receptor 2 (TfR2): (i) has a mitochondrial targeting sequence;(ii) is localized, in part, in mitochondria;and (iii) protein is selectively expressed in nigral dopamine neurons in rats.
Aim i : We will determine the sequence of cell types that accumulate iron after rotenone using the in vivo model and organotypic midbrain slice cultures, and we vAW ultimately assess this in human postmortem specimens across Braak staging.
Aim 2 : We will characterize (i) the oxidation state and distributions of Tf and TfR2 in the rotenone brain, (ii) the functional consequences of Tf oxidation, and (iii) ultimately, the distributions and oxidation states of these proteins in human specimens.
Aim 3 : We will assess the functional role of TfR2 by overexpressing or silencing the TfR2 gene under basal conditions and with rotenone treatment. Outcomes to be measured include: aspects of iron homeostasis, oxidative stress, a-synuclein/cytochrome c interactions, activation of cell death and protective mechanisms and cell viability.
Aim 4 : Lastly, we will manipulate - via viral-mediated gene transfer - proteins that regulate or chelate iron. We will look at the effects of manipulating ferritin and frataxin on rotenone-induced toxicity. We believe this project will elucidate (i) the mechanisms by which iron accumulates in PD and (ii) its role in PD pathogenesis.
|Verma, Manish; Callio, Jason; Otero, P Anthony et al. (2017) Mitochondrial Calcium Dysregulation Contributes to Dendrite Degeneration Mediated by PD/LBD-Associated LRRK2 Mutants. J Neurosci 37:11151-11165|
|Tapias, Victor; Hu, Xiaoping; Luk, Kelvin C et al. (2017) Synthetic alpha-synuclein fibrils cause mitochondrial impairment and selective dopamine neurodegeneration in part via iNOS-mediated nitric oxide production. Cell Mol Life Sci 74:2851-2874|
|Di Maio, Roberto; Barrett, Paul J; Hoffman, Eric K et al. (2016) ?-Synuclein binds to TOM20 and inhibits mitochondrial protein import in Parkinson's disease. Sci Transl Med 8:342ra78|
|Van Laar, Victor S; Berman, Sarah B; Hastings, Teresa G (2016) Mic60/mitofilin overexpression alters mitochondrial dynamics and attenuates vulnerability of dopaminergic cells to dopamine and rotenone. Neurobiol Dis 91:247-61|
|Hu, Xiaoming; Leak, Rehana K; Shi, Yejie et al. (2015) Microglial and macrophage polarization—new prospects for brain repair. Nat Rev Neurol 11:56-64|
|Greenamyre, J Timothy; Sanders, Laurie H; Gasser, Thomas (2015) Fruit flies, bile acids, and Parkinson disease: a mitochondrial connection? Neurology 85:838-9|
|Zharikov, Alevtina D; Cannon, Jason R; Tapias, Victor et al. (2015) shRNA targeting ?-synuclein prevents neurodegeneration in a Parkinson's disease model. J Clin Invest 125:2721-35|
|Lee, Jang-Won; Tapias, Victor; Di Maio, Roberto et al. (2015) Behavioral, neurochemical, and pathologic alterations in bacterial artificial chromosome transgenic G2019S leucine-rich repeated kinase 2 rats. Neurobiol Aging 36:505-18|
|Hu, Xiaoming; Liou, Anthony K F; Leak, Rehana K et al. (2014) Neurobiology of microglial action in CNS injuries: receptor-mediated signaling mechanisms and functional roles. Prog Neurobiol 119-120:60-84|
|Sanders, Laurie H; McCoy, Jennifer; Hu, Xiaoping et al. (2014) Mitochondrial DNA damage: molecular marker of vulnerable nigral neurons in Parkinson's disease. Neurobiol Dis 70:214-23|
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