Saturday, May 10, 2025
5/10/2025
Contribution of astrocytes to mutant FUS-linked Amyotrophic Lateral Sclerosis - ABSTRACT The goal of this project is to identify the mechanisms by which mutations in Fused in Sarcoma (FUS) induce pathological and pathogenic changes in astrocytes in FUS-linked Amyotrophic Lateral Sclerosis (FUS-ALS). Astrocytes are known to contribute to disease progression in some, but not all, forms of ALS and, until recently, not much was known about the role of astrocytes in FUS-ALS. Our lab has recently published the first in vitro evidence that astrocytes expressing mutant forms of FUS (mutFUS), but not wild-type FUS, exert toxicity on motor neurons through activation of the NFkB pathway leading to the release of secreted factor(s), and primarily TNFα (Kia & McAvoy et al., GLIA, 2018). In a TNFα−dependent manner, motor neurons exposed to the conditioned medium of mutFUS astrocytes show AMPA receptor alterations that sensitize them to excitotoxic damage, leading to cell death. Activation of astrocytic NFkB and TNFα release seems to be specific to mutFUS-ALS, underscoring the importance of dissecting disease mechanisms specific to each form of ALS in order to develop tailored therapies. In this proposal, we will focus on mutFUS-ALS and will study (1) the mechanisms by which disease-casuative mutations in FUS alter astrocyte biology and (2) how mutant FUS expressing astrocyte affect the viability of other cells in the spinal cord in vivo. The ultimate goal is to identify key pathways targeted by mutFUS to eventually develop specific therapies. Ultimately, our models of FUS-ALS may serve as a platform for a comparative analysis with models mimicking other forms of ALS, so to identify genotype- specific vs. converging and more global mechanisms of disease pathogenesis. For our studies, we will use in vitro and in vivo models consisting of (1) primary rodent astrocytes transduced with different FUS mutations as well as iPSc-derived astrocytes from FUS patients; (2) an in vivo mouse model of mutFUS ALS. The in vitro systems will allow us to dissect the precise mechanisms by which mutFUS targets the astrocytes and to determine how mutFUS alters astrocyte biology in patients. The mouse model will allow us to study how mutFUS astrocytes affect the cellular environment in a complex in vivo setting.
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