Autophagy in lysosomal storage disorders

Abstract

Lysosomes are ubiquitous intracellular organelles that have an acidic internal pH, and play crucial roles in cellular clearance. Numerous functions depend on normal lysosomes, including the turnover of cellular constituents, cholesterol homeostasis, downregulation of surface receptors, inactivation of pathogenic organisms, repair of the plasma membrane and bone remodeling. Lysosomal storage disorders (LSDs) are characterized by progressive accumulation of undigested macromolecules within the cell due to lysosomal dysfunction. As a consequence, many tissues and organ systems are affected, including brain, viscera, bone and cartilage. The progressive nature of phenotype development is one of the hallmarks of LSDs. In recent years biochemical and cell biology studies of LSDs have revealed an ample spectrum of abnormalities in a variety of cellular functions. These include defects in signaling pathways, calcium homeostasis, lipid biosynthesis and degradation and intracellular trafficking. Lysosomes also play a fundamental role in the autophagic pathway by fusing with autophagosomes and digesting their content. Considering the highly integrated function of lysosomes and autophagosomes it was reasonable to expect that lysosomal storage in LSDs would have an impact upon autophagy. The goal of this review is to provide readers with an overview of recent findings that have been obtained through analysis of the autophagic pathway in several types of LSDs, supporting the idea that LSDs could be seen primarily as “autophagy disorders.”

Trehalose reduces retinal degeneration, neuroinflammation and storage burden caused by a lysosomal hydrolase deficiency

“…TFEB overexpression promotes lysosomal proliferation and enhances degradative capabilities against lysosomal or autophagic substrates (such as glycosaminoglycans, polyQ-expanded HTT (huntingtin), and ceroid lipopigments), and rescues affected neurons in animal models of proteinopathies [17,21–27]. Because impairment of autophagy has been described in several models of neuropathic lysosomal storage disorders caused by lysosomal enzyme deficiencies [28,29], we hypothesized that enhancement of autophagy might counteract disease progression in these disorders. We tested our hypothesis by using a mouse model of MPS IIIB (B6.129S6- Naglu tm1Efn /J) and trehalose, a known activator of autophagy [30–40] that reaches the mouse brain when provided orally [41], and evaluated the efficacy of this strategy through electrophysiological, behavioral, neuropathological and molecular analyses.…”

Defects in calcium homeostasis and mitochondria can be reversed in Pompe disease

“…12 Lysosomes are major players in the autophagic process, and lysosomal storage disorders (LSDs) have been recently classified as disorders of autophagy-accumulation of any substrate in the lysosome triggers an expansion of the lysosomal compartment and affects the fusion of lysosomes and autophagosomes. 13,14 The impaired autophagosomal-lysosomal fusion is likely to affect autophagic degradation of mitochondria. Indeed, mitochondrial dysfunction has been reported in several LSDs: GM1-gangliosidosis 15, 16 and mucolipidosis II, III, and IV, 17,18 neuronal ceroid lipofuscinosis or Batten disease, 19 Gaucher disease, 20 and multiple sulfatase deficiency.…”

High sphingomyelin levels induce lysosomal damage and autophagy dysfunction in Niemann Pick disease type A

“…However, recent evidence indicates that deficient degradation in LSDs also derives from alterations in endosomal and autophagosomal pathways, which flow into the lysosomal system. 2 Autophagy is the process involved in the degradation of cytoplasmic organelles and cytosolic components. The best characterized kind of autophagy, macroautophagy, starts with the formation of an isolation membrane enveloping cytoplasmic cargoes to generate an autophagosome.…”

“…3,4 Deficiencies in different steps of the autophagic pathway have been recently described in several LSDs. 2 These evidences led to the hypothesis that removal of autophagic buildup could be a suitable approach to treat these diseases. However, these findings also underscored the need to independently define the nature of the autophagy impairment for each LSD.…”

“…2 Niemann Pick disease type A (NPA) is a sphingolipidosis caused by loss of function mutations in the gene SMPD1 encoding for the acid sphingomyelinase (ASM). 5 This enzyme catalyzes sphingomyelin (SM) conversion into ceramide in lysosomes.…”