N370S‐GBA1 mutation causes lysosomal cholesterol accumulation in Parkinson's disease

Abstract

Our results support a connection between the loss of β-glucocerebrosidase-1 function, cholesterol accumulation, and the disruption of cellular homeostasis in GBA1-PD. Our work reveals new insights into the cellular pathways underlying PD pathogenesis, providing evidence that GBA1-PD shares common features with lipid-storage diseases. © 2017 International Parkinson and Movement Disorder Society.

Beyond the lysosome: Cholesterol role on endoplasmic reticulum and lipid droplets in Parkinson's disease

“…García‐Sanz and colleagues strengthen the association between GBA and cholesterol homeostasis in PD, in agreement with recent studies reporting accumulation of total cholesterol in response to GCase knockdown or loss of activity . By confirming free cholesterol accumulation in the lysosomes from the fibroblasts of PD patient's carrying the N370S‐ GBA1 mutation, the researchers also corroborate previous findings in endolysosomes from homozygous N370S‐ GBA1 fibroblasts .…”

Can Leucine‐Rich Repeat Kinase 2 Inhibition Benefit GBA–Parkinson's Disease?

“…Sanyal and colleagues used astrocytes carrying the GBA p.D409V mutation knocked in to the endogenous murine locus. As expected, the cells from these animals have lower GCase activity although total GCase levels remain unaltered, suggesting a possible retention of the protein in a prelysosomal compartment, as previously reported in fibroblasts isolated from PD patients harboring the GBA‐N370S mutation . The authors then cataloged lysosomal activity using a number of different measures.…”

Lysosomal membrane permeabilization and cell death

“…In certain neurodegenerative conditions, lysosomal lipid alterations may underlie susceptibility to lysosomal destabilization and LDCD. For example, cholesterol accumulation and lysosomal damage have been described in fibroblasts from PD patients carrying the N370S/wild‐type GBA1 mutation, and high sphingomyelin levels induce lysosomal damage and autophagy dysfunction in Niemann‐Pick disease type A patient fibroblasts . Protecting the lysosomal membrane by increasing the interaction between Hsp70 and the lipid BMP reverses lysosomal dysfunction in Niemann‐Pick disease …”