Project 2: Mechanisms of Neurodegeneration in alpha-Synuclein Transgenic Mice. While the causes of Parkinson's disease (PD) is not known, genetic and biochemical abnormalities of alpha- synuclein are directly implicated in the pathogenesis PD and other alpha-synucleinopathies. Transgenic (Tg) mice expressing the A53T mutant human alpha-synuclein develop adult-onset disease with a progressive motoric dysfunction leading to death. The affected mice exhibit many of the features of human alpha- synucleinopathies, including aberrant aggregation of a-Syn and neurodegeneration in subcortical regions. Characterization of alpha-synucleinopathy in Tg mice reveal signs of oxidative stress, including mitochondrial abnormalities. Because both mitochondrial abnormalities and oxidative stress are implicated in the pathogenesis of PD and other a-synucleinopathies, we will examine the pathological relationships between oxidative stress and alpha-synucleinopathies in Hua-Syn Tg mice.
First (Aim 1), we will determine whether the disease in the Tg mice is associated with oxidative stress, particularly associated with mitochondrial abnormalities.
Second (Aims 2 and 3), we will test if oxidative stress act in concert with alpha-synuclein abnormalities exacerbate alpha-synuclein pathology and neurodegeneration. Finally, we hypothesize that oxidative stress causes activation of c-Abl and c-Abl activation directly participates in the disease. We will show that alpha-synuclein pathology is associated with c-Abl activation in mice and in human PD cases. We will show that lack of c-Abl function attenuates neurodegeneration in alpha-synuclein Tg mice. Finally, we will show that c-Abl phosphorylates alpha-synuclein and such alpha-synuclein is preferentially found associated with the aggregates. In addition, we will collaborate with Project 1 to determine if alpha- synuclein pathology leads to defects in parkin function and with Project 3 to determine linke between mutant LRRK2 and alpha-synuclein pathology in vivo. These studies will provide in vivo experimental tests of processes that are directly relevant to the pathogenesis of human alpha-synucleinopathies and may lead to new therapeutic approaches.
Alpha-synuclein abnormalities are implicated as the events responsible for cell death in PD and other related diseases. Thus, understanding how alpha-synuclein abnormalities cause neuronal death in brain will provide better understanding about PD and may lead to therapeutic approaches that will target the underlying processes that are responsible for PD.
|Mills, Kelly A; Mari, Zoltan; Bakker, Catherine et al. (2016) Gait function and locus coeruleus Lewy body pathology in 51 Parkinson's disease patients. Parkinsonism Relat Disord 33:102-106|
|Mao, Xiaobo; Ou, Michael Tianhao; Karuppagounder, Senthilkumar S et al. (2016) Pathological Î±-synuclein transmission initiated by binding lymphocyte-activation gene 3. Science 353:|
|Geiger, Joshua T; Arthur, Karissa C; Dawson, Ted M et al. (2016) C9orf72 Hexanucleotide Repeat Analysis in Cases with Pathologically Confirmed Dementia with Lewy Bodies. Neurodegener Dis 16:370-2|
|Mata, Ignacio F; Leverenz, James B; Weintraub, Daniel et al. (2016) GBA Variants are associated with a distinct pattern of cognitive deficits in Parkinson's disease. Mov Disord 31:95-102|
|Rosenthal, Liana S; Drake, Daniel; Alcalay, Roy N et al. (2016) The NINDS Parkinson's disease biomarkers program. Mov Disord 31:915-23|
|Jo, Junghyun; Xiao, Yixin; Sun, Alfred Xuyang et al. (2016) Midbrain-like Organoids from Human Pluripotent Stem Cells Contain Functional Dopaminergic and Neuromelanin-Producing Neurons. Cell Stem Cell 19:248-57|
|Karuppagounder, Senthilkumar S; Xiong, Yulan; Lee, Yunjong et al. (2016) LRRK2 G2019S transgenic mice display increased susceptibility to 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP)-mediated neurotoxicity. J Chem Neuroanat 76:90-97|
|Davis, Marie Y; Johnson, Catherine O; Leverenz, James B et al. (2016) Association of GBA Mutations and the E326K Polymorphism With Motor and Cognitive Progression in Parkinson Disease. JAMA Neurol 73:1217-1224|
|Nucifora Jr, Frederick C; Nucifora, Leslie G; Ng, Chee-Hoe et al. (2016) Ubiqutination via K27 and K29 chains signals aggregation and neuronal protection of LRRK2 by WSB1. Nat Commun 7:11792|
|Mills, Kelly A; Mari, Zoltan; Pontone, Gregory M et al. (2016) Cognitive impairment in Parkinson's disease: Association between patient-reported and clinically measured outcomes. Parkinsonism Relat Disord 33:107-114|
Showing the most recent 10 out of 206 publications