Lysosomal storage diseases and the heat shock response: convergences and therapeutic opportunities

Abstract

The lysosomal storage diseases (LSDs) describe a heterogenous family of rare inherited diseases caused by mutations in lysosomal proteins and are characterized by accumulation of macromolecules or monomeric compounds inside organelles of the endo-lysosomal system ( 1-3 ). The LSDs present complex disease phenotypes with the mechanisms leading to pathology being poorly understood, as the disease and extent of pathology seem to depend on the spatiotemporal accumulation of substrates which have a variety of downstream effects depending on their cellular and physiological context ( Table 1 ). It is thus diffi cult to generalize for the LSDs, but as the origin of the diseases in all cases is a genetic lesion, which most often causes a misfolded dysfunctional protein, the cellular processes and responses related to misfolded proteins have to be considered as an integral part of the etiology of any of the diseases. Thus, the shared mechanistic principle of disturbed protein homeostasis and the fact that many LSDs also show an overlap of potentially toxic storage compounds might explain why the LSDs, despite their various monogenetic origins, share a number of cellular and clinical manifestations including perturbed lysosomal traffi cking and autophagy, increased oxidative stress, impaired calcium homeostasis, loss of lysosomal stability, increased 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 defi ned 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 p...

Progranulin Recruits HSP70 to β-Glucocerebrosidase and Is Therapeutic Against Gaucher Disease

“…In addition, HSP70, known to be crucial in unlocking protein disaggregation (Nillegoda et al, 2015, Nillegoda and Bukau, 2015), was isolated as one of numerous GCase-associated proteins dependent on the presence of PGRN in our unbiased proteomic screen. Interestingly, the interaction between GCase and HSP70, as well as their involvement in GD, had been reported previously (Lu et al, 2011, Yang et al, 2014, Ingemann and Kirkegaard, 2014), although the nature of this association was unclear. In addition, the binding of PGRN to HSP70 was also independently reported (Almeida et al, 2011).…”

Arimoclomol as a potential therapy for neuronopathic Gaucher Disease

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