Lysosomes constitute the main degradative organelle in eukaryotic cells, enclosing a wide repertoire of acidic hydrolases capable of digesting macromolecules such as glycoproteins and lipids (Luzio et al., 2007). Importantly, lysosomes not only degrade and recycle material but utilize it to collect information about changing environmental conditions, to integrate multiple signals, and to generate a response to communicate these changes to the nucleus, allowing cellular adaptation (Perera and Zoncu, 2016; Raben and Puertollano, 2016).
Lysosomal dysfunction is the underlying cause of a class of metabolic disorders known as lysosomal storage diseases (LSDs) (Platt et al., 2018). There are over 50 clinical variants of LSDs, and their combined prevalence is estimated to be 1 in 5,000 live births. LSDs are characterized by progressive accumulation of undigested material inside lysosomes leading to cellular dysfunction in multiple organs, including brain, muscle, bone, skin, heart, and spleen, among others. Most LSDs are caused by mutations that result in decreased enzymatic activity of a particular lysosomal hydrolase, causing a blockage in a specific catabolic pathway and accumulation of a particular type of storage material. However, LSDs can also result from alterations in accessory proteins (co-chaperones and co-factors), proteins implicated in the trafficking of lysosomal enzymes from the endoplasmic reticulum (ER) to lysosomes, and lysosomal transmembrane proteins, which play an important role in the transport and recycling of metabolites and ions as well as in maintaining an optimal lysosomal lumen environment (Marques and Saftig, 2019). Finally, genetic mutations that affect the biogenesis, trafficking, or maturation of lysosome-related organelles (LROs) have also been linked to disease (Huizing et al., 2008).
Pathogenesis
LSDs are caused by mutations in a wide range of genes coding for lysosomal proteins and several non-lysosomal proteins involved in lysosomal function. In the instance of specific enzyme deficiencies, a particular type of material accumulates in the lysosome (primary storage). Based on the nature of the primary storage, LSDs are classified as sphingolipidoses, mucopolysaccharidoses, glycoproteinoses, etc. In addition, a number of materials (most often phospholipids, glycosphingolipids, and cholesterol), which are not directly connected to the primary defect, accumulate in several LSDs (secondary storage). The disruption of lysosomal function by the accumulated storage can trigger a chain of downstream events that affect the ability of the cell to survive. The inability of lysosomes to fuse with autophagosomes leads to macroautophagy impairment; this results in accumulation of aberrant mitochondria and toxic protein aggregates (tertiary storage). Downregulation of chaperone-mediated autophagy (CMA) has also been reported in several LSDs. A global disturbance of the endosomal/lysosomal system and autophagy leads to signaling abnormalities, defects in calcium homeostasis, oxidative stress, and inflammation (Platt et al., 2012). This pathogenic cascade has been described in many but not all LSDs. LSDs present with a multisystem phenotype, and many are associated with neurodegeneration.
Current Therapeutic Interventions
The number of treatments for LSDs has increased dramatically in the past decade (Platt, 2018; Parenti et al., 2015). Some of these, such as bone marrow and hematopoietic stem cell transplantation, enzyme replacement, substrate reduction, and chaperone therapies are already available for patients with several LSDs. Gene therapy, a powerful option for monogenic disorders such as LSDs, is becoming a reality; it is designed to provide a correct copy of the defective gene. Enzyme enhancement therapy is a strategy aimed at improving the folding and increasing the residual activity of mutant proteins in the ER. Substrate reduction therapy employs small molecules that slow the rate of storage accumulation by inhibiting its synthesis. Enzyme replacement therapy relies on receptor-mediated lysosomal trafficking of exogenous recombinant enzymes. Finally, several experimental approaches have been used in preclinical studies to address the autophagy defect and signaling abnormalities.
ACKNOWLEDGMENTS
This work was supported by the Intramural Research Program of the National Heart, Lung, and Blood Institute of the NIH.
ABBREVIATIONS
- AGA
aspartylglucosaminidase
- ARSA
arylsulfatase A
- ARSB
arylsulfatase B
- ASAH1
N-acylsphingosine amidohydrolase 1
- Asn
asparagine
- ATP13A2
ATPase cation transporting 13A2
- Cer
ceramide
- CLN
ceroid lipofuscinosis, neuronal
- CMA
chaperone-mediated autophagy
- CTNS
cystinosin, lysosomal cystine transporter
- CTSA
cathepsin A
- CTSD
cathepsin D
- CTSF
cathepsin F
- D-IdoA
D-iduronic acid
- DNAJC5
DnaJ heat shock protein family (Hsp40) member C5
- FGly
formylglycine
- Fuc
fucose
- FUCA1
alpha-L-fucosidase 1
- GAA
glucosidase alpha, acid
- Gal
galactose
- GALC
galactosylceramidase
- GalNac
N-acetylgalactosamine
- GALNS
galactosamine (N-acetyl)-6-sulfatase
- GBA
glucosylceramidase beta
- GLA
galactosidase alpha
- GLB1
galactosidase beta 1
- Glc
glucose
- GlcA
glucuronic acid
- GlcNac
N-acetylglucosamine
- GM1
GM1 ganglioside
- GM2
GM2 ganglioside
- GM2A
GM2 activator deficiency
- GM3
GM3 ganglioside
- GNPTAB
N-acetylglucosamine-1-phosphate transferase subunits alpha and beta
- GNPTG
N-acetylglucosamine-1-phosphate transferase subunit gamma
- GNS
glucosamine (N-acetyl)-6-sulfatase
- GUSB
glucuronidase beta
- HEXA
hexosaminidase subunit alpha
- HEXB
hexosaminidase subunit beta
- HGSNAT
heparan-alpha-glucosaminide N-acetyltransferase
- HSCT
hematopoietic stem cell transplantation
- HSP
heat shock protein
- HYAL1
hyaluronidase 1
- IDS
iduronate 2-sulfatase
- IDUA
alpha-L-iduronidase
- ISSD
infantile free sialic acid storage disease
- KCTD7
potassium channel tetramerization domain containing 7
- L-IdoA
L-iduronic acid
- LAMP
lysosomal-associated membrane protein
- LE
lysosomal enzyme
- LIPA
lipase A, lysosomal acid type
- LYST
lysosomal trafficking regulator
- M6PR
mannose-6-phosphate receptor
- MAN2B1
mannosidase alpha class 2B member 1
- MANBA
mannosidase beta
- MCOLN1
mucolipin 1
- MFSD8
major facilitator superfamily domain containing 8
- ML
mucolipidosis
- MPS
mucopolysaccharidoses
- MYO5A
myosin VA
- N-Ac
N-acetyl
- NAGA
alpha-N-acetylgalactosaminidase
- NAGLU
N-acetyl-alpha-glucosaminidase
- NANA
N-acetylneuraminic acid
- NEU1
Neuraminidase 1
- NPC
NPC intracellular cholesterol transporter
- P
phosphate
- PPT1
palmitoyl-protein thioesterase 1
- PSAP
prosaposin
- S
sulfate
- SCARB2
scavenger receptor class B member 2
- SGSH
N-sulfoglucosamine sulfohydrolase
- SLC17A5
solute carrier family 17 member 5
- SMPD1
sphingomyelin phosphodiesterase 1
- SUMF1
sulfatase modifying factor 1
- TPP1
tripeptidyl peptidase 1
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