Study Of Systemic Inflammation In A Mouse Model Of Spinal Muscular Atrophy

Background and Objective: Spinal muscular atrophy(SMA)is an inherited neurodegenerative disease.In recent years,numerous studies revealed widespread defects in peripheral organs,which contribute to the complete picture of SMA,especially of severe forms.Our previous studies have shown critical importance of peripheral pathologies in premature death and motor neuron loss in SMA mice,demonstrating involvement of cell-nonautonomous mechanisms in motor neuron degeneration.This project aims to understand the mechanisms underlying peripheral defects in a severe SMA mouse model and explore how peripheral defects affect spinal-cord motor neurons.Experimental Design and Methods: The severe Taiwanese SMA mouse model is used as experimental animals.First,we employ H&E staining for various peripheral organs,particularly the liver,to identify tissue and cell defects.Second,we take advantage of various molecular and biochemical techniques such as q RT-PCR,Western blot,ELISA,etc.to identify critical genes and proteins that cause tissue defects.Finally,based on the identified signaling pathways downstream of survival of motor neuron(SMN),we design new therapeutic approaches to treat SMA.Results: Through thorough pathological study on peripheral tissues of severe Taiwanese SMA mice,we find serious structural impairments in the intestine,which lead to increased intestinal epithelial permeability,resulting in more bacterial loads in peripheral organs.The bacterial invasion,together with enhanced apoptosis in several tissues that has been recently reported,induces systemic inflammation in the new-born SMA pups,which may be an important contributor to multi-organs dysfunction and motor neuron death in the context of SMA.Conclusion: The severe Taiwanese SMA mouse model develops systemic inflammation after birth,which aggravates SMA phenotype including premature death and motor neuron degeneration.The key genes we identified offer new targets for therapeutic intervention against SMA.