Cytosolic sphingolipids and lysosome reactivation in neurodegenerative diseases
type: CreativeWork
description: Glucosylceramide (GlcCer) is one of the simplest glycosphingolipids (GSLs) synthesized at the cytosolic face of cis-Golgi and translocated to the plasma membrane and organelle lumen. The glucocerebrosidases degrade GlcCer in the cytosol and lysosome. GlcCer has been suggested to be an activator of vATPase, leading to proper endolysosomal acidification. Lysosomal storage disorders (LSDs), are caused by the defective activity of lysosomal proteins, including the accumulation of unmetabolized substrates. The accumulation of substrates is thought to initiate a complex pathogenic cascade that is responsible for disease pathology, Chapter1 firstly summarizes the synthesis of glycolipids and their transportation to lysosomes for degradation and recycling back into the Golgi; however, in the case of LSDs, this is defective. Furthermore, it discusses how impaired endolysosomal acidification and lipid imbalance can be linked and common to LSDs. Chapter 2 depicts decreased lysosomal acidification and increased size in Gaucher/Parkinson's and various other LSD patient fibroblasts. Then it studies whether these defects can be corrected by altering cytosolic GlcCer. Chapter 3 shows decreased MCS between the ER/lysosomes, increased MCS between lysosomes/ the mitochondria in NPCD, and investigates if increasing cytosolic GlcCer can correct these defects. Furthermore, it tests a bank of putative cholesterol transport inhibitors in NPCD based on reports of high cholesterol levels contributing to mitochondrial dysfunction. A chemoproteomics approach has found several proteins that bind ceramides and glycolipids. Chapter 4 sought to confirm the interactions between ceramides/glycolipids and their binding proteins using molecular modelling and gene expression analysis.
abstract: Glucosylceramide (GlcCer) is one of the simplest glycosphingolipids (GSLs) synthesized at the cytosolic face of cis-Golgi and translocated to the plasma membrane and organelle lumen. The glucocerebrosidases degrade GlcCer in the cytosol and lysosome. GlcCer has been suggested to be an activator of vATPase, leading to proper endolysosomal acidification. Lysosomal storage disorders (LSDs), are caused by the defective activity of lysosomal proteins, including the accumulation of unmetabolized substrates. The accumulation of substrates is thought to initiate a complex pathogenic cascade that is responsible for disease pathology, Chapter1 firstly summarizes the synthesis of glycolipids and their transportation to lysosomes for degradation and recycling back into the Golgi; however, in the case of LSDs, this is defective. Furthermore, it discusses how impaired endolysosomal acidification and lipid imbalance can be linked and common to LSDs. Chapter 2 depicts decreased lysosomal acidification and increased size in Gaucher/Parkinson's and various other LSD patient fibroblasts. Then it studies whether these defects can be corrected by altering cytosolic GlcCer. Chapter 3 shows decreased MCS between the ER/lysosomes, increased MCS between lysosomes/ the mitochondria in NPCD, and investigates if increasing cytosolic GlcCer can correct these defects. Furthermore, it tests a bank of putative cholesterol transport inhibitors in NPCD based on reports of high cholesterol levels contributing to mitochondrial dysfunction. A chemoproteomics approach has found several proteins that bind ceramides and glycolipids. Chapter 4 sought to confirm the interactions between ceramides/glycolipids and their binding proteins using molecular modelling and gene expression analysis.
author: Bhardwaj, Meenakshi
license: https://dora.dmu.ac.uk/bitstreams/895e13f7-bcb0-4c0b-b2a6-9d9884d627ad/download
date published: 2023-03
date modified: 2026-07-24T06:18:44Z
provider: De Montfort University
publisher: Networked Digital Library of Theses and Dissertations
type: WebPage
source organization: De Montfort University