The role of glial cells in the pathogenesis of Parkinsoní»s disease
Parkinsoní»s disease (PD) is one of the most common neurodegenerative diseases. It is characterized by degeneration of dopaminergic neurons in the substantia nigra. Currently there is no effective treatment available that significantly delays the disease progression, due to our incomplete understanding of the mechanisms underlying neurodegeneration. It is generally believed that PD results from the accumulation of mis-folded proteins in the substantia nigra. Although PD pathogenesis is considered as í░neuron-mediatedí▒, emerging evidence indicates that glial cells (astrocytes and microglia) may play important roles in the development and progression of PD.
We have previously shown that classical dopamine D1 and D2 receptors play distinct functional roles in astrocytes from that in neuronal cells under physiological conditions. Astrocytic DA receptors are important in the modulation of fibroblast growth factor-2 (FGF-2) expression which contributes to the enhanced survival of DA neurons (Li, et al. FASEB J, 2006). Astrocytic PI-linked D1 like receptor, atypic DA receptor, is also involved in the regulation of FGF-2 expression via calcium oscillation (Zhang, et al. J. Neurosci., 2009). We have extended our physiological studies to the rodent models of PD. We found that astrocytic dopamine D2 receptor activation normally suppresses neuroinflammation in the striatum via an alphaB-crystallin-dependent manner. Thus, astrocytes likely play a previously unexpected but critical role in the modulation of neuroinflammation (Shao, et al. Nature, 2013). We are currently investigating the roles of distinct subpopulations of glial cells in the neuroinflammation and their contributions to the pathogenesis of PD by using molecular and cellular biology approaches in combination with behavioral assays. Our hope is that our work will help us to better understand the biological basis of brain aging and neurodegenerative diseases so that more effective therapeutic preventions and interventions will be established.
Regulation of dopamine release and reuptake and its roles in drug addiction.
Midbrain DA neurons are involved in the control of voluntary movements and in the regulation of emotion, cognition and consciousness. They are affected in many neurological and psychiatric disorders, including Parkinsoní»s disease, schizophrenia and drug addiction. However, the molecular mechanisms underlying the regulation of DA homeostasis have not been fully understood. We hypothesized that midbrain DA neuron activities are regulated in a brain-region-specific manner and identification of genes specific for this brain region may help decode complex function of nigral DA neurons and develop novel treatments for PD and other associated brain disorders.
Previously, we have identified a set of ventral mesencephalon-enriched genes that regulate mouse midbrain DA neuron development (Yin, et al. J. Neurosci., 2009). We have also identified a group of genes that are highly expressed in the substantia nigra of adult rat brain (Zhou, et al. Neurobiol Aging, 2011). Emerging evidence indicates that some of these midbrain-enriched genes may be involved in the maintenance and regulation of DA homeostasis selectively in the adult midbrain. We are currently investigating their roles in the process of dopamine release, reuptake and cocaine-induced drug addiction. We utilize a wide range of approaches in these projects including biochemistry, molecular and cellular biology techniques, electrophysiology, histology, behavioral assays and mouse genetic models.