Open AccessSphingolipid metabolism governs Purkinje cell patterned degeneration in Atxn1[82Q]/+ mice
Author(s) -
François G. C. Blot,
Wilhelmina H. J. J. Krijnen,
Sandra den Hoedt,
Catarina Osório,
Joshua J. White,
Monique Mulder,
Martijn Schonewille
Publication year - 2021
Publication title -
proceedings of the national academy of sciences of the united states of america
Language(s) - English
Resource type - Journals
eISSN - 1091-6490
pISSN - 0027-8424
DOI - 10.1073/pnas.2016969118
Subject(s) - neurodegeneration , purkinje cell , sphingolipid , biology , cerebellum , neuroprotection , sphingosine , microbiology and biotechnology , neuroscience , medicine , biochemistry , receptor , disease
Significance Neuronal subtypes are differentially affected by neuropathologies. For example, Purkinje cells, the principal neurons of the cerebellum, can be divided in subpopulations based on their sensitivity to pathological insult. However, the molecular mechanisms explaining why, among seemingly identical neurons, some will degenerate while others survive remain unknown. Here, we analyzed, in a disease model of cerebellar neurodegeneration, the metabolism of sphingolipids, complex lipids involved in cell apoptosis, and found that specific sphingolipids accumulate in the cerebellar region primarily affected by neurodegeneration. Preventing this accumulation by disrupting sphingolipid metabolism via genetic mutation caused a neuroprotective effect on subpopulations of Purkinje cells. Thus, our data indicate that sphingolipid metabolism is involved in the predisposition of neuronal subtypes to neurodegeneration.