TGR5 and FXR receptors in motor degeneration: Molecular mechanism, crosstalk pathways and therapeutic prospects.

Motor neuron degeneration in disorders such as amyotrophic lateral sclerosis, spinal muscular atrophy, and Parkinson's disease is increasingly recognized as a consequence of disrupted metabolic, mitochondrial, and inflammatory balance. There is emerging data that bile acid receptors - Takeda G-protein-coupled receptor 5 (TGR5) and Farnesoid X receptor (FXR) are key regulators that combine systemic metabolism with neuronal survival. These receptors modulate the mitochondrial biogenesis, oxidative stress responses, and glial inflammatory signaling and coordinate gut-liver-brain crosstalk. Their malfunction leads to an unaffected energy metabolism, increased reactive oxygen species, and neuroinflammation, thereby accelerating the death of motor neurons. Their dysfunction results in impaired energy metabolism increased reactive oxygen species and neuroinflammation, accelerating motor neuron death. Pharmacological activation of TGR5 and FXR improves mitochondrial integrity reduces cytokines driven toxicity and preserves neuromuscular junction stability in preclinical models. However, translational opportunities are dampened by some factors such as restriction of bioavailability of the central nervous system, receptor variation and metabolic systemic interactions. To clarify, the TGR5 -FXR signaling axis would provide a mechanistic model of how to develop metabolism-based therapeutics that can simultaneously supplement mitochondrial protection, immunologic mangling, and neuro-specific to energetic homeostasis in motor neuron disease.