RT Journal Article
SR Electronic
T1 Neuroinflammation in neuronopathic Gaucher disease: Role of microglia and NK cells
JF bioRxiv
FD Cold Spring Harbor Laboratory
SP 2022.05.13.491834
DO 10.1101/2022.05.13.491834
A1 Chandra Sekhar Boddupalli
A1 Shiny Nair
A1 Glenn Belinsky
A1 Joseph Gans
A1 Erin Teeple
A1 Tri-Hung Nguyen
A1 Sameet Mehta
A1 Lilu Guo
A1 Martin L Kramer
A1 Jiapeng Ruan
A1 Hongge Wang
A1 Matthew Davison
A1 D.J Vidyadhara
A1 Zhang Bailin
A1 Katherine Klinger
A1 Pramod K. Mistry
YR 2022
UL http://biorxiv.org/content/early/2022/05/16/2022.05.13.491834.abstract
AB Background Neuronopathic Gaucher Disease (nGD) is a rare neurodegenerative disorder caused by biallelic mutations in Gba, and buildup of glycosphingolipids in lysosomes. Neuronal injury and cell death are prominent pathological features, however the role of Gba in individual cell types and involvement of microglia, blood derived macrophages and immune infiltrates in nGD pathology remains enigmatic.Methods Here, using single cell resolution of mouse nGD brains, we found induction of neuroinflammation pathways involving microglia, NK cells, astrocytes, and neurons.Results Targeted rescue of Gba in microglia and in neurons, respectively in Gba deficient, nGD mice reversed the buildup of glucosylceramide (GlcCer) and glucosylsphingosine (GlcSph), concomitant with amelioration of neuroinflammation, reduced level of serum neurofilament light chain (Nf-L) and improved survival. The levels of bioactive lipid, GlcSph was strongly correlated with serum Nf-L and ApoE in nGD mouse models as well as GD patients. Gba rescue in microglia/macrophage compartment prolonged survival, that was further enhanced upon treatment with brain permeant inhibitor of glucosylceramide synthase, effects mediated via improved glycosphingolipid homeostasis and reversal of neuroinflammation involving activation of microglia, brain macrophages and NK cells.Conclusions Together, our study delineates individual cellular effects of Gba deficiency in nGD brains, highlighting the central role of neuroinflammation driven by microglia activation and the role of brain permeant small molecule glucosylceramide inhibitor in reversing complex multidimensional pathophysiology of nGD. Our findings advance disease biology whilst identifying compelling biomarkers of nGD to improve patient management, enrich clinical trials and illuminate therapeutic targets.Funding: Research grant from Sanofi Genzyme; other support includes R01NS110354.Yale Liver Center P30DK034989, pilot project grant.Competing Interest StatementPKM receives research funding and travel support from Sanofi Genzyme. JG, ET, T-H.N, LG, MK, HW, MD, ZB and KK are employees of Sanofi Genzyme.