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.
|Martin, Ian; Kim, Jungwoo Wren; Dawson, Valina L et al. (2014) LRRK2 pathobiology in Parkinson's disease. J Neurochem 131:554-65|
|Dawson, Ted M; Dawson, Valina L (2014) Parkin plays a role in sporadic Parkinson's disease. Neurodegener Dis 13:69-71|
|Lee, Yun-Il; Giovinazzo, Daniel; Kang, Ho Chul et al. (2014) Protein microarray characterization of the S-nitrosoproteome. Mol Cell Proteomics 13:63-72|
|Siuda, Joanna; Jasinska-Myga, Barbara; Boczarska-Jedynak, Magdalena et al. (2014) Early-onset Parkinson's disease due to PINK1 p.Q456X mutation--clinical and functional study. Parkinsonism Relat Disord 20:1274-8|
|Fatokun, Amos A; Dawson, Valina L; Dawson, Ted M (2014) Parthanatos: mitochondrial-linked mechanisms and therapeutic opportunities. Br J Pharmacol 171:2000-16|
|Stafa, Klodjan; Tsika, Elpida; Moser, Roger et al. (2014) Functional interaction of Parkinson's disease-associated LRRK2 with members of the dynamin GTPase superfamily. Hum Mol Genet 23:2055-77|
|Martin, Ian; Kim, Jungwoo Wren; Lee, Byoung Dae et al. (2014) Ribosomal protein s15 phosphorylation mediates LRRK2 neurodegeneration in Parkinson's disease. Cell 157:472-85|
|Tsika, Elpida; Glauser, Liliane; Moser, Roger et al. (2014) Parkinson's disease-linked mutations in VPS35 induce dopaminergic neurodegeneration. Hum Mol Genet 23:4621-38|
|Pirooznia, Sheila K; Dawson, Valina L; Dawson, Ted M (2014) Motor neuron death in ALS: programmed by astrocytes? Neuron 81:961-3|
|Lasagna-Reeves, Cristian A; Sengupta, Urmi; Castillo-Carranza, Diana et al. (2014) The formation of tau pore-like structures is prevalent and cell specific: possible implications for the disease phenotypes. Acta Neuropathol Commun 2:56|
Showing the most recent 10 out of 141 publications