The goal to effectively treat neurodegenerative disorders will require an understanding not only of intrinsic neuronal dysfunction, but also of how non-neuronal cells contribute to neuronal dysfunction. Spinocerebellar ataxia type 1 (SCA1), is a fatal, dominantly inherited neurodegenerative disease characterized by degeneration of Purkinje neurons in the cerebellum. Despite intense focus on neuron intrinsic mechanisms, pathogenesis of SCA1 remains incompletely understood and there are no effective therapies available for SCA1 patients. Astroglia play fundamental roles in nearly all aspects of neuronal function, and research in other neurodegenerative diseases demonstrated that they contribute to disease pathogenesis. We have previously shown that cerebellar astroglia are activated pre-symptomatically in the mouse models of SCA1, and that their activation correlates with neuronal dysfunction and disease progression. Our new preliminary data indicate that astroglia have a bi-modal, disease-stage dependent role in the pathogenesis of SCA1. We have found that astroglia are beneficial pre-symptomatically, whereas they become harmful after the onset of symptoms. Moreover we have found that these different effects of astroglia are regulated by NF-?B signaling, one of the key transcriptional regulators of astrogliosis. We have also found that early in disease NF-?B signaling enhances the expression of neurosupportive genes brain derived neurotrophic factor (BDNF) and potassium channel Kir4.1 in astroglia, while later in SCA1, NF-?B decreases expression of these genes. The objective of this proposal is to test our central hypothesis that early in disease astroglial NF-?B signaling regulates neuroprotective astroglial phenotype, but switches to regulating harmful astroglial phenotype late in disease. We propose that mechanistically, NF-?B alters critical supportive functions of astroglia, such as the ability to promote neuronal survival (BDNF), and maintain homeostasis levels of extracellular ions and neurotransmitters (Kir4.1) in a stage-of disease specific manner.
Spinocerebellar ataxia type 1 (SCA1) is a fatal, dominantly inherited neurodegenerative disease with no available therapies. We propose to determine the extent to which astroglia, cells critical for neuronal function contribute to the pathogenesis of SCA1, to increase our understanding of disease process and inform design of effective therapies for SCA1 patients.
