Dysregulation of autophagy as a common mechanism in lysosomal storage diseases

Abstract

The lysosome plays a pivotal role between catabolic and anabolic processes as the nexus for signalling pathways responsive to a variety of factors, such as growth, nutrient availability, energetic status and cellular stressors. Lysosomes are also the terminal degradative organelles for autophagy through which macromolecules and damaged cellular components and organelles are degraded. Autophagy acts as a cellular homeostatic pathway that is essential for organismal physiology. Decline in autophagy during ageing or in many diseases, including late-onset forms of neurodegeneration is considered a major contributing factor to the pathology. Multiple lines of evidence indicate that impairment in autophagy is also a central mechanism underlying several lysosomal storage disorders (LSDs). LSDs are a class of rare, inherited disorders whose histopathological hallmark is the accumulation of undegraded materials in the lysosomes due to abnormal lysosomal function. Inefficient degradative capability of the lysosomes has negative impact on the flux through the autophagic pathway, and therefore dysregulated autophagy in LSDs is emerging as a relevant disease mechanism. Pathology in the LSDs is generally early-onset, severe and life-limiting but current therapies are limited or absent; recognizing common autophagy defects in the LSDs raises new possibilities for therapy. In this review, we describe the mechanisms by which LSDs occur, focusing on perturbations in the autophagy pathway and present the latest data supporting the development of novel therapeutic approaches related to the modulation of autophagy.

TRAPPC11 functions in autophagy by recruiting ATG2B‐WIPI4/WDR45 to preautophagosomal membranes

“…This is likely due to their role in biosynthetic membrane trafficking. 23,54 While it is possible that altered lysosomal activity could affect formation of autolysosomes, 73 we do not favor this possibility for several reasons.…”

Use of human iPSCs and kidney organoids to develop a cysteamine/mTOR inhibition combination therapy to treat cystinosis

“…63 The observation that sucrose loading induces the equivalent phenotype in non-cystinotic iPSCs and that other lysosomal storage diseases show basal autophagy flux defects points to the intralysosomal accumulation of indigestible material as a generic cause of the flux defect. [64][65][66][67] Our finding that CTNS-iPSCs upregulate a number of genes in the autophagy pathway suggests that compromised basal autophagy leads to the activation of transcriptional feedback mechanisms to compensate for the reduced flux.…”

The neuronal ceroid lipofuscinosis protein Cln7 regulates neural development from the post-synaptic cell

“…Defects in the effectiveness of the autophagy pathway are associated with many forms of neurodegenerative disease, including forms of NCL (25) and impairment of autophagy is known to cause a reduction in synapse size similar to that seen in the Cln7 mutants (21). In cultured cells, Cln7 is associated predominantly with lysosomes, which are essential mediators of autophagy and mutations affecting lysosomal function lead to a block in autophagic flux.…”