SnapShot: Lysosomal Storage Diseases

SnapShot: Lysosomal Storage Diseases José A. Martina, Nina Raben, and Rosa Puertollano Cell and Developmental Biology Center, National Heart, Lung, and Blood Institute, National Institutes of Health, Bethesda, MD, USA FGly

Pathogenesis

Sulfatase

Endoplasmic reticulum

Mutations

Cys

? CLN6 (CLN6)

Sulfatase

X

Sandhoff disease (HEXB) CLN8 (CLN8)

Golgi

CLN14 (KCTD7) ?

LE

CLN4 (DNAJC5) Hsc70 co-chaperone

Cell death and organ damage

CLN11 (GRN)

CLN3 (CLN3) ?

Lysosome Niemann-Pick C (NPC1, NPC2) Cholesterol

Danon disease (LAMP2) CMA

CLN5 (CLN5) ?

Eye

Muscle

Liver

Pompe disease (GAA) Salla disease ISSD (SLC17A5) Sialic acid

Skin

Glycogen

Lymph node

Bone/joints/ bone marrow Cystine Cystinosis (CTNS)

Lysosome-related organelle disorders

Proteins

X

X

Griscelli syndrome 1 (MYO5A)

Hydrolases

Griscelli syndrome 2 (RAB27A)

Ca2+, Fe2+ Mucolipidosis IV (MCOLN1)

Melanosome

Cholesterol Fatty acids

Metals CLN12 (ATP13A2)

Lipids? Action myoclonus-renal failure syndrome (SCARB2)

Cellular compartments targeted by the current therapeutic interventions Nucleus Gene therapy Stop codon read-through HSP70 activators Enzyme enhancement therapy Pharmacological chaperons Proteostasis regulators HSP70-based therapy

ER

Golgi

Lysosome

Enzyme replacement therapy Bone marrow/ HSC transplantation Cholesterol removal Correction of downstream pathways Autophagy-targeting therapy Stimulation of lysosomal exocytosis (TFEB/TFE3)

Substrate reduction therapy

X

NANA

GM3

Gal Glc Cer Lactosylceramide

Calcium modulation therapy Correction of abnormal signaling (mTORC1)

602 Cell 180, February 6, 2020 © 2020 Elsevier Inc.  DOI: https://doi.org/10.1016/j.cell.2020.01.017

X

Glc Cer Glucocerebroside Gaucher disease (GBA)

Mucopolysaccharidoses Keratan sulfate

S L-IdoA Glc D-IdoA Glc (n) S N-S S N-Ac Hunter syn. (IDS) MPSII S L-IdoA Glc D-IdoA Glc (n) N-S S N-Ac Hurler, Hurler-Scheie, MPSI Scheie syn. (IDUA) S Glc D-IdoA Glc (n) N-S S N-Ac Sanfilippo syn. A (SGSH) MPSIIIA S Glc D-IdoA Glc (n) N S N-Ac Sanfilippo syn. C (HGSNAT) MPSIIIC S Glc D-IdoA Glc (n) S N-Ac N-Ac Sanfilippo syn. B MPSIIIB (NAGLU) S D-IdoA Glc (n) S N-Ac S D-IdoA Glc (n) N-Ac Sly disease (GUSB) MPSVII S Glc (n) N-Ac Sanfilippo syn. D (GNS) MPSIID

S S S Gal Glc Gal Glc (n) N-Ac N-Ac Morquio syn. MPSIVA (GALNS) S S Gal Glc Gal Glc (n) N-Ac N-Ac

X

X

X

Dense bodies

X (GM2A)

Heparan sulfate

X

Io n c h a n nels

? CLN7 (MFSD8)

GM2

Sphingosine

X

Amino acids

Glc Cer

Gal Glc Cer

X

X

GBA binding

Chediak-Higashi dsease (LYST)

Lytic granule

Glucose

Acid lipase deficiency (LIPA)

Cholesteryl esters Triglycerides

Hermansky-Pudlak disease types 1-9 (HPS1-HPS9)

X

X

X

X

CLN1 (PPT1) CLN2 (TPP1) CLN10 (CTSD) CLN13 (CTSF)

T r a n s po r t e r s

Lung

Spleen

GM1

Tay-Sachs disease (HEXA)

Cer Ceramide Niemann-Pick A/B (SMPD1) Farber disease (ASAH1)

Plasma membrane

M6PR

Heart

X

X

Sphingomyelin

P

P LE

Glc Cer

X

Progranulin

Major affected organs/tissues

NANA

Gal Cer Galactocerebroside Krabbe disease (GALC)

X

LE

Inflammatory response Immune abnormalities Neurodegeneration

Gal Cer -O3S Sulfatide Metachromatic leukodystrophy (ARSA, PSAP)

Mucolipidosis II a/β (GNPTAB) Mucolipidosis III a/β (GNPTAB) Mucolipidosis III γ (GNPTG) P LE

NANA

GalNAc Gal

Gal Gal Glc Cer Trihexosylceramide Fabry disease (GLA)

LE

Signaling abnormalities

Kidney

Gal Glc Cer

Gal

Globoside LE

Autophagy impairment: accumulation of aberrant proteins and mitochondria (tertiary storage)

Brain

Gal

GM1 gangliosidosis (GLB1) GalNAc

Lipids and cholesterol accumulation (secondary storage)

Nerves

Multiple sulfatase deficiency (SUMF1)

LE

Substrate accumulation (primary storage)

GalNAc Gal

Sphingolipidoses

X

Morquio syn. MPSIVB (GLB1) S S Glc Gal Glc (n) N-Ac N-Ac

X

Dermatan sulfate S Glc D-IdoA N-Ac

Glc (n) N-Ac

Maroteaux-Lamy syn. (ARSB) Glc D-IdoA N-Ac

Glc (n) N-Ac

Hyaluronan GlcA

Glc GlcA N-Ac

Natowicz syn. (HYAL1) GlcA

Glc (n) N-Ac NANA

NANA

X Gal

Gal

GlcNAc

GalNAc

X X

Man

X

Glc (n) N-Ac

X MPSIX

Glc (n) N-Ac

Glycoproteinoses Sialidosis type I, (NEU1) Sialidosis type II (NEU1) Galactosialidosis (CTSA) Schindler disease (NAGA)

Man

Man

X GlcNAc X Fuc GlcNAc

X

X MPSVI

Asn Protein

α-Mannosidosis (MAN2B1) β-Mannosidosis (MANBA) Fucosidosis (FUCA1) Aspartylglucosaminuria (AGA)

See online version for legends and references

SnapShot: Lysosomal Storage Diseases José A. Martina, Nina Raben, and Rosa Puertollano Cell and Developmental Biology Center, National Heart, Lung, and Blood Institute, National Institutes of Health, Bethesda, MD, USA 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. 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, alphaL-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-alphaglucosaminidase; 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. ACKNOWLEDGMENTS This work was supported by the Intramural Research Program of the National Heart, Lung, and Blood Institute of the NIH. REFERENCES Huizing, M., Helip-Wooley, A., Westbroek, W., Gunay-Aygun, M., and Gahl, W.A. (2008). Disorders of lysosome-related organelle biogenesis: clinical and molecular genetics. Annu. Rev. Genomics Hum. Genet. 9, 359–386. Luzio, J.P., Pryor, P.R., and Bright, N.A. (2007). Lysosomes: fusion and function. Nat. Rev. Mol. Cell Biol. 8, 622–632. Marques, A.R.A., and Saftig, P. (2019). Lysosomal storage disorders - challenges, concepts and avenues for therapy: beyond rare diseases. J. Cell Sci. 132, jcs221739. Parenti, G., Andria, G., and Ballabio, A. (2015). Lysosomal storage diseases: from pathophysiology to therapy. Annu. Rev. Med. 66, 471–486. Perera, R.M., and Zoncu, R. (2016). The Lysosome as a Regulatory Hub. Annu. Rev. Cell Dev. Biol. 32, 223–253. Platt, F.M. (2018). Emptying the stores: lysosomal diseases and therapeutic strategies. Nat. Rev. Drug Discov. 17, 133–150. Platt, F.M., Boland, B., and van der Spoel, A.C. (2012). The cell biology of disease: lysosomal storage disorders: the cellular impact of lysosomal dysfunction. J. Cell Biol. 199, 723–734. Platt, F.M., d’Azzo, A., Davidson, B.L., Neufeld, E.F., and Tifft, C.J. (2018). Lysosomal storage diseases. Nat. Rev. Dis. Primers 4, 27. Raben, N., and Puertollano, R. (2016). TFEB and TFE3: Linking Lysosomes to Cellular Adaptation to Stress. Annu. Rev. Cell Dev. Biol. 32, 255–278.

602.e1 Cell 180, February 6, 2020 © 2020 Elsevier Inc.  DOI: https://doi.org/10.1016/j.cell.2020.01.017