Abstract
Lysosomes play a vital role in the maintenance of cellular homeostasis through the recycling of cell constituents, a key metabolic function which is highly dependent on the correct function of the lysosomal hydrolases and membrane proteins, as well as correct membrane lipid stoichiometry and composition. The critical role of lysosomal functionality is evident from the severity of the diseases in which the primary lesion is a genetically defined loss-of-function of lysosomal hydrolases or membrane proteins. This group of diseases, known as lysosomal storage diseases (LSDs), number more than 50 and are associated with severe neurodegeneration, systemic disease, and early death, with only a handful of the diseases having a therapeutic option. Another key homeostatic system is the metabolic stress response or heat shock response (HSR), which is induced in response to a number of physiological and pathological stresses, such as protein misfolding and aggregation, endoplasmic reticulum stress, oxidative stress, nutrient deprivation, elevated temperature, viral infections, and various acute traumas. Importantly, the HSR and its cardinal members of the heat shock protein 70 family has been shown to protect against a number of degenerative diseases, including severe diseases of the nervous system. The cytoprotective actions of the HSR also include processes involving the lysosomal system, such as cell death, autophagy, and protection against lysosomal membrane permeabilization, and have shown promise in a number of LSDs. This review seeks to describe the emerging understanding of the interplay between these two essential metabolic systems, the lysosomes and the HSR, with a particular focus on their potential as a therapeutic target for LSDs.
Highlights
Lysosomes play a vital role in the maintenance of cellular homeostasis through the recycling of cell constituents, a key metabolic function which is highly dependent on the correct function of the lysosomal hydrolases and membrane proteins, as well as correct membrane lipid stoichiometry and composition
The following sections will aim to break down these cellular events into their major constituents with a focus on processes where the heat shock response (HSR) and HSP70 are considered to have a potential therapeutic relevance, including the initial events of enzyme misfolding, endoplasmic reticulum (ER) stress, and unfolded protein responses (UPRs), as well as the processes of substrate accumulation, lysosomal membrane permeabilization (LMP), increased oxidative stress, and cell death (Fig. 1)
This study showed marked efficacy for some of the histone deacetylase inhibitor (HDACi) toward reduced cholesterol accumulation and increased cholesterol transport; whereas others had a more limited effect, likely due to the different inhibitory constants toward individual histone deacetylase (HDAC)
Summary
Neuronal cell death (in vivo) Regulation of myelin Apoptosis Anti-apoptotic Regulation of myelin Enhance GM-CSF induced proliferation of monocytes UPR MMP, apoptosis, and ROS generation Inhibits SERCA activity Stimulates neurite outgrowth Regulates nuclear calcium and displays a cytoprotective role Positive role in induction of long term potentiation Inhibits calcium uptake via SERCA, alters calcium homeostasis Apoptosis Survival of motor neurons ROS generation Neuronal cell death and ROS generation Apoptosis Anti-apoptotic effect on cortical neurons Enhance neurite outgrowth Alters calcium homeostasis of neurons Cell death and ROS generation Apoptosis in oligodendrocytes MMP and neuronal apoptosis Enhance neurite outgrowth Calcium influx Enhance neurite outgrowth Positive role in induction of long term potentiation Inhibition of cholesterol efflux Prevents phago-lysosomal fusion LMP Stimulates calcium release LMP and cell death Lipid raft integrity Inflammation Stimulates NO synthase in neural astrocytes Apoptosis Autophagy Programmed cell death at the plasma membrane Increases membrane stability Myelination Activator of the immune system, anti-tumorigenic Apoptosis Increases ROS Correlates with disease severity Inhibits ␣-Gal A activity Promotes proliferation Protects from LPS toxicity Mitochondrial membrane potential and ATP synthesis Protect from apoptosis Neurodegeneration Apoptosis neuronal cells Demyelination Generates ROS and induces cell death Stimulates calcium release via RyaR Apoptosis. HSP70 has, on its own, been shown to promote cell survival by inhibiting lysosomal membrane permeabilization (LMP), increasing lysosomal catabolism, and preventing cell death and a number of other events associated with stress-induced cell death [11,12,13,14]. The following sections will aim to break down these cellular events into their major constituents with a focus on processes where the HSR and HSP70 are considered to have a potential therapeutic relevance, including the initial events of enzyme misfolding, ER stress, and unfolded protein responses (UPRs), as well as the processes of substrate accumulation, LMP, increased oxidative stress, and cell death (Fig. 1)
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