The role of brain innate immune response in lysosomal storage disorders: fundamental process or evolutionary side-effect?

Vitner, Einat B

Sphingolipidoses are diseases caused by mutations in genes responsible for sphingolipid degradation and thereby lead to sphingolipid accumulation. Most sphingolipidoses have a neurodegenerative manifestation characterized by innate immune activation in the brain. However, the role of the immune response in disease progression is ill-understood. In contrast to infectious diseases, immune activation is unable to eliminate the offending agent in sphingolipidoses resulting in ineffective, chronic inflammation. This paradox begs two fundamental questions: why has this immune response evolved in sphingolipidoses? What role does it play in disease progression? Here, starting from the observation that sphingolipids are elevated also in infectious diseases, I discuss the possibility that activation of the brain immune response by sphingolipids has evolved as a part of the immune response against pathogens and plays no major role in sphingolipidoses.