Complement Turning Violent in Ultra-Rare Genetic Disorder

Abstract Sandhoff disease (SD) is an ultra-rare lysosomal storage disorder (LSD), which affects ~ 1/1000, 000 live birth. SD caused by genetic deficiency of beta (β) Hexosaminidase and resulting excess central nervous system (CNS) synthesis GM2 ganglioside (GM2) its impact on neuron death. The exact mechanisms underlying such GM2-driven death are unknown in SD. Glucosylceramide (GC) induced complement 5a (C5a) C5aR1 activation causes tissue inflammation experimental clinical Gaucher disease. Additionally, C5a-C5aR1 axis was found to sparks CNS neurodegeneration several brain diseases including, intracerebral hemorrhage, traumatic injury, myasthenia gravis, amyotrophic lateral sclerosis, neuromyelitis optica spectrum, Alzheimer, Huntington’s diseases. Here, we determined the increased levels C5a a hexosaminidase inhibitor (HABI)-induced mouse model SD, when compared vehicle (PBS) injected WT control mice. Also, HABI-induced showed microglial cells activation, massive generation pro-inflammatory cytokines loss neurons, To assess relevance for targeted β with HAB-I −/−mice. Strikingly, as HABI-injected mice, −/−mice marked reduction cell production cytokines, neurons. These data suggest that critical driver neuroinflammation No Funding