1. Nurr1 determines the preferential degeneration of midbrain dopaminergic neurons in a Parkinsons disease mouse model The functional properties and survival of midbrain DA neurons rely on the constitutive activities of nuclear receptor related 1 (Nurr1), also known as nuclear receptor subfamily 4, group A, member 2 (NR4A2) (Perlmann and Wallen-Mackenzie, 2004). Nurr1 controls the expression of tyrosine hydroxylase (TH), dopamine transporter (DAT), receptor tyrosine kinase Ret, and other dopaminergic genes critical for the function and maintenance of midbrain DA neurons. Genetic ablation of Nurr1 from the germ cells results in a lack of mature midbrain DA neurons and premature lethality (Zetterstrom et al., 1997), while deletion of Nurr1 after the terminal differentiation of midbrain DA neurons leads to a PD-like progressive loss of midbrain DA neuron marker proteins and eventually the death of midbrain DA neurons (Kadkhodaei et al., 2009). The expression of Nurr1 is dynamically regulated at both the transcriptional and post-translational levels. Nuclear factor-κB (NF-κB) and cAMP response element-binding protein (CREB) pathways have been suggested to regulate the transcription of Nurr1 mRNA (McEvoy et al., 2002). Meanwhile, multiple post-translational modifications such as phosphorylation, ubiquitination (Jo et al., 2009), sumoylation (Galleguillos et al., 2004), and perhaps acetylation (Kang et al., 2010) have been found to modulate the stability and function of Nurr1 protein in various cellular events. More interestingly, in postmortem PD brains the expression of Nurr1 is significantly decreased in the midbrain DA neurons that also contain alpha-syn-positive inclusions (Chu et al., 2006). However, the observations in PD brains do not address whether the decreased Nurr1 levels are just an end-stage consequence or a more dynamic α-syn-dependent pathogenic mechanism directly involved in the disease. To investigate the pathogenic mechanism of alpha-syn-dependent dopaminergic dysfunction in vivo, we generated a new line of alpha-syn transgenic mice by selectively driving the expression of PD-related human alpha-syn A53T missense mutation in the midbrain DA neurons. The mutant mice developed profound movement disorders, as well as robust and progressive midbrain DA neuron degeneration, recapitulating the key clinical and neuropathological features of PD. In addition to the neuronal loss, the structure/function of ER/Golgi networks and autophagosome/lysosome pathways, and the release of transmitter dopamine were also significantly affected in the midbrain DA neurons of mutant mice. More importantly, over-expression of alpha-syn substantially abrogated the transcription of Nurr1 mRNA and evoked the proteasome-dependent degradation of Nurr1 protein in midbrain DA neurons. Together, our findings demonstrate the significance of Nurr1 inhibition in alpha-syn-mediated preferential vulnerability of midbrain DA neurons in PD. As a proof-of-principle, the blockage of proteasome-dependent degradation of Nurr1 rescued the alpha-syn-induced loss of midbrain DA neurons. * Manuscript is in preparation for the above data. 2. Astrocytic expression of Parkinson's disease-related A53T alpha-synuclein causes neurodegeneration in mice. Parkinson's disease (PD) is the most common movement disorder. While neuronal deposition of α-synuclein serves as a pathological hallmark of PD and Dementia with Lewy Bodies, α-synuclein-positive protein aggregates are also present in astrocytes. The pathological consequence of astrocytic accumulation of α-synuclein, however, is unclear. Here we show that PD-related A53T mutant α-synuclein, when selectively expressed in astrocytes, induced rapidly progressed paralysis in mice. Increasing accumulation of α-synuclein aggregates was found in presymptomatic and symptomatic mouse brains and correlated with the expansion of reactive astrogliosis. The normal function of astrocytes was compromised as evidenced by cerebral microhemorrhage and down-regulation of astrocytic glutamate transporters, which also led to increased inflammatory responses and microglial activation. Interestingly, the activation of microglia was mainly detected in the midbrain, brainstem and spinal cord, where a significant loss of dopaminergic and motor neurons was observed. Consistent with the activation of microglia, the expression level of cyclooxygenase 1 (COX-1) was significantly up-regulated in the brain of symptomatic mice and in cultured microglia treated with conditioned medium derived from astrocytes over-expressing A53T α-synuclein. Consequently, the suppression of COX-1 activities extended the survival of mutant mice, suggesting that excess inflammatory responses elicited by reactive astrocytes may contribute to the degeneration of neurons. Our findings demonstrate a critical involvement of astrocytic α-synuclein in initiating the non-cell autonomous killing of neurons, suggesting the viability of reactive astrocytes and microglia as potential therapeutic targets for PD and other neurodegenerative diseases.
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