Sunday, May 11, 2025
5/11/2025
Modulation of astrocyte-mediated neurotoxicity by NR1D1 in ALS models - Abstract ALS or Lou Gehrig's disease is the most common adult-onset motor neuron disease, characterized by the progressive degeneration of motor neurons in the spinal cord, brain stem, and motor cortex. Motor neuron death leads to muscle weakness and paralysis, usually causing death in one to five years after symptoms onset. The molecular mechanisms responsible for motor neuron degeneration in ALS remain uncertain. However, several lines of evidence indicate that dysfunction of glial cells significantly contributes to the neurodegenerative process. Astrocytes, key regulators of central nervous system homeostasis, have been shown to play a major role in the progression of the disease. Accordingly, in cell culture models, astrocytes isolated from ALS mouse models or astrocytes differentiated from fibroblast-derived induced pluripotent stem cells (iPSCs) from sporadic and familial ALS patients, induce motor neuron death. Astrocytes have a key role in the metabolic support of neurons, and lack of metabolic flexibility and mitochondrial dysfunction are hallmarks of ALS astrocytes. We recently showed that NR1D1 plays a critical role in the regulation of astrocyte-motor neuron interaction. NR1D1 is a member of the nuclear receptor superfamily and it is an essential component of the molecular clock in mammals. NR1D1 is also a known repressor of metabolic and inflammatory genes, and has been shown to regulate mitochondrial number and function, glucose and lipid metabolism, and inflammation during normal and pathological conditions. We recently reported that NR1D1 expression decreases in the spinal cord of symptomatic ALS mice. Moreover, we showed that the knockdown of Nr1d1 expression in primary mouse spinal cord astrocyte cultures, or in iPSC- derived human astrocytes, activates NF-kB signaling and induces a pro-inflammatory phenotype that is detrimental for the survival of co-cultured motor neurons. In addition, our preliminary data shows that iPSC- derived astrocytes from ALS patients display lower levels of NR1D1 expression when compared to astrocytes derived from healthy controls. In this proposal, we will investigate the role of NR1D1 in the regulation of astrocyte- motor neuron interaction and the therapeutic potential of targeting NR1D1 in ALS. We will perform an unbiased multi-omic analysis to outline the mechanism by which NR1D1 downregulation induces a neurotoxic phenotype in human iPSC-derived astrocytes (Aim 1). In addition, we will use different approaches to evaluate the effect of modulating NR1D1 expression on the progression of the disease in an ALS mouse model (Aims 2 and 3). The results obtained will contribute to the current understanding of the mechanisms involved in the toxicity of astrocytes towards motor neurons in ALS. In addition, this proposal will establish the therapeutic value of targeting NR1D1 to slow or halt the progression of the disease in an ALS mouse model.
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