Background and Specific Aims: A large exonic deletion and a point mutation (L166P) in the DJ-1 gene were initially reported in two different families with autosomal early-onset PD. DJ-1-associated PD appears to manifest via a loss of function mechanism, because the first reported mutations contained either large exonic deletions resulting in an absence of protein and mRNA, or a L166P mutation that resulted in rapid protein degradation. To better understand DJ-1 and its role in PD, we developed a DJ-1 gene knockout mouse. Thus, our specific aims for this project are:
Aim 1 : To generate and characterize DJ-1 knockout mice;
Aim 2 : To study the function of DJ-1.
Aim 3 : To investigate the genetic interactions between DJ-1 and other PD-related genetic mutations. Motor behavior, dopaminergic trans-mission, and neuropathology will be examined in these DJ-1 knockout mice. Meanwhile, we will study the function of DJ-1 protein by determining the subcellular localization of DJ-1 via immunocytochemistry of cultured midbrain neurons and identifying DJ-1-associated proteins via immunoprecipitation. Progress Report and Future Directions: To investigate the physiological functions of DJ-1 in vivo, we generated DJ-1 knockout (DJ-1 -/-) mice. Younger (<1 year) DJ-1 -/- mice were hypoactive and had mild gait abnormalities. Older DJ-1 -/-;, however, showed decreased body weight and grip strength and more severe gait irregularities compared to wild-type littermates. The basal level of extracellular dopamine, evoked dopamine release and dopamine receptor D2 sensitivity appeared normal in the striatum of DJ-1 -/- mice, which was consistent with similar results between DJ-1 -/-;and controls in behavioral paradigms specific for the dopaminergic system. An examination of spinal cord, nerve and muscle tissues failed to identify any pathological changes that were consistent with the noted motor deficits. Taken together, our findings suggest that loss of DJ-1 leads to progressive behavioral changes without significant alterations in nigrostriatal dopaminergic and spinal motor systems. Although the loss of DJ-1 dose not lead to DA neuron degeneration in mice, mice lacking DJ-1 exhibit a deficit in dopaminergic signaling in the striatum. Because the hippocampus contains relatively high levels of DJ-1, and PD patients are often cognitively impaired, we evaluated the effects of DJ-1 deficiency on the plasticity of hippocampal CA1 synapses. LTP was slightly impaired and LTD was abolished in DJ-1 -/- mice, whereas DJ-1+/- mice exhibited no alterations in synaptic plasticity. The dopamine receptor D2/3 agonist quinpirole rescued LTD in DJ-1 -/- mice, suggesting a role for impaired dopaminergic signaling in the hippocampal LTD deficit. As an extension of our previous work on DJ-1 KO mice, we are interested in studying the role of DJ-1 in the pathogenesis of other PD-related genetic mutations. We have recently successfully developed several novel lines of transgenic mice that selectively express PD-related alpha-synuclein A53T and LRRK2 G2019S mutations in the midbrain DA neurons. The alpha-synuclein A53T transgenic mice developed PD-like clinical phenotypes at an age dependent manner. It would be interesting to investigate whether the presence of DJ-1 will affect the progression of mutant alpha-synucelin-mediated motor behavioral and neuropathological abnormalities. We will crossbreed the alpha-synuclein transgenic mice with DJ-1 KO mice to generate a cohort of alpha-synuclein transgenic mice in the DJ-1 null background. We expect to observe an acceleration of alpha-synuclein-mediated neuropathology in the absence of DJ-1. We will then investigate the molecular mechanism of how DJ-1 modulates the cytotoxicity induced by alpha-synuclein by a combination of in vivo mouse modeling and in vitro neurobiology approaches.
| Chandran, Jayanth S; Lin, Xian; Zapata, Agustin et al. (2008) Progressive behavioral deficits in DJ-1-deficient mice are associated with normal nigrostriatal function. Neurobiol Dis 29:505-14 |
| van der Brug, Marcel P; Blackinton, Jeff; Chandran, Jayanth et al. (2008) RNA binding activity of the recessive parkinsonism protein DJ-1 supports involvement in multiple cellular pathways. Proc Natl Acad Sci U S A 105:10244-9 |
| Wang, Yue; Chandran, Jayanth S; Cai, Huaibin et al. (2008) DJ-1 is essential for long-term depression at hippocampal CA1 synapses. Neuromolecular Med 10:40-5 |
