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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\u2010understood. 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 (SLs) are elevated also in infectious diseases, I discuss the possibility that the activation of the brain immune response by SLs has evolved as a part of the immune response against pathogens and plays no major role in sphingolipidoses.<\/jats:p>","DOI":"10.1002\/1873-3468.13980","type":"journal-article","created":{"date-parts":[[2020,11,1]],"date-time":"2020-11-01T03:29:11Z","timestamp":1604201351000},"page":"3619-3631","update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":8,"title":["The role of brain innate immune response in lysosomal storage disorders: fundamental process or evolutionary side effect?"],"prefix":"10.1002","volume":"594","author":[{"ORCID":"https:\/\/orcid.org\/0000-0001-8578-8551","authenticated-orcid":false,"given":"Einat B.","family":"Vitner","sequence":"first","affiliation":[{"name":"Department of Infectious Diseases Israel institute for Biological 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