Pathogenesis of Mucopolysaccharidoses, an Update

Overview

Journal Int J Mol Sci

Publisher MDPI

Specialties Biochemistry
Chemistry
Molecular Biology

Date 2020 Apr 9

PMID 32260444

Citations 50

Authors

Simona Fecarotta

Antonietta Tarallo

Carla Damiano

Nadia Minopoli

Giancarlo Parenti

Affiliations

Soon will be listed here.

Abstract

The recent advancements in the knowledge of lysosomal biology and function have translated into an improved understanding of the pathophysiology of mucopolysaccharidoses (MPSs). The concept that MPS manifestations are direct consequences of lysosomal engorgement with undegraded glycosaminoglycans (GAGs) has been challenged by new information on the multiple biological roles of GAGs and by a new vision of the lysosome as a signaling hub involved in many critical cellular functions. MPS pathophysiology is now seen as the result of a complex cascade of secondary events that lead to dysfunction of several cellular processes and pathways, such as abnormal composition of membranes and its impact on vesicle fusion and trafficking; secondary storage of substrates; impairment of autophagy; impaired mitochondrial function and oxidative stress; dysregulation of signaling pathways. The characterization of this cascade of secondary cellular events is critical to better understand the pathophysiology of MPS clinical manifestations. In addition, some of these pathways may represent novel therapeutic targets and allow for the development of new therapies for these disorders.

Citing Articles

Oral trehalose improves histological and behavior symptoms of mucopolysaccharidosis type II in iduronate 2-sulfatase deficient mice.

Lee H, Han J, Jeong R, Kang Y, Choi B, Kim S Sci Rep. 2025; 15(1):4882.

PMID: 39929944 PMC: 11811122. DOI: 10.1038/s41598-025-88362-0.

Heparan sulfate in cerebrospinal fluid as a biomarker to assess disease severity and for treatment monitoring in patients with Mucopolysaccharidosis Type II: a position statement.

Giugliani R, de Siqueira A, Santos E, Leao E, Carvalho G, Schmitz Ferreira Santos M Orphanet J Rare Dis. 2024; 19(1):436.

PMID: 39593190 PMC: 11590453. DOI: 10.1186/s13023-024-03463-9.

α-mannosidosis diagnosis in Brazilian patients with MPS-like symptoms.

Marins M, Curiati M, Perez Gomes C, Martin R, Nicolicht-Amorim P, Yamamoto J Orphanet J Rare Dis. 2024; 19(1):439.

PMID: 39593065 PMC: 11600758. DOI: 10.1186/s13023-024-03419-z.

Adeno-Associated Virus Gene Transfer Ameliorates Progression of Skeletal Lesions in Mucopolysaccharidosis IVA Mice.

Herreno-Pachon A, Sawamoto K, Stapleton M, Khan S, Piechnik M, Alvarez J Hum Gene Ther. 2024; 35(23-24):955-968.

PMID: 39450470 PMC: 11659441. DOI: 10.1089/hum.2024.096.

Oncological Aspects of Lysosomal Storage Diseases.

Lugowska A Cells. 2024; 13(19.

PMID: 39404425 PMC: 11475748. DOI: 10.3390/cells13191664.

References

Pereira V, Martins A, Micheletti C, DAlmeida V . Mutational and oxidative stress analysis in patients with mucopolysaccharidosis type I undergoing enzyme replacement therapy. Clin Chim Acta. 2007; 387(1-2):75-9. DOI: 10.1016/j.cca.2007.09.008. View

Cosma M, Pepe S, Annunziata I, Newbold R, Grompe M, Parenti G . The multiple sulfatase deficiency gene encodes an essential and limiting factor for the activity of sulfatases. Cell. 2003; 113(4):445-56. DOI: 10.1016/s0092-8674(03)00348-9. View

Hara T, Nakamura K, Matsui M, Yamamoto A, Nakahara Y, Suzuki-Migishima R . Suppression of basal autophagy in neural cells causes neurodegenerative disease in mice. Nature. 2006; 441(7095):885-9. DOI: 10.1038/nature04724. View

Tomatsu S, Yasuda E, Patel P, Ruhnke K, Shimada T, Mackenzie W . Morquio A syndrome: diagnosis and current and future therapies. Pediatr Endocrinol Rev. 2014; 12 Suppl 1:141-51. PMC: 4259875. View

Walkley S, Vanier M . Secondary lipid accumulation in lysosomal disease. Biochim Biophys Acta. 2008; 1793(4):726-36. PMC: 4382014. DOI: 10.1016/j.bbamcr.2008.11.014. View

Hunter C . A Rare Disease in Two Brothers. Proc R Soc Med. 2009; 10(Sect Study Dis Child):104-16. PMC: 2018097. View

Bonini N, Giasson B . Snaring the function of alpha-synuclein. Cell. 2005; 123(3):359-61. DOI: 10.1016/j.cell.2005.10.017. View

Ballabio A, Bonifacino J . Lysosomes as dynamic regulators of cell and organismal homeostasis. Nat Rev Mol Cell Biol. 2019; 21(2):101-118. DOI: 10.1038/s41580-019-0185-4. View

Walkley S . Secondary accumulation of gangliosides in lysosomal storage disorders. Semin Cell Dev Biol. 2004; 15(4):433-44. DOI: 10.1016/j.semcdb.2004.03.002. View

10.

Simons K, Gruenberg J . Jamming the endosomal system: lipid rafts and lysosomal storage diseases. Trends Cell Biol. 2000; 10(11):459-62. DOI: 10.1016/s0962-8924(00)01847-x. View

11.

Lloyd-Evans E, Platt F . Lysosomal Ca(2+) homeostasis: role in pathogenesis of lysosomal storage diseases. Cell Calcium. 2011; 50(2):200-5. DOI: 10.1016/j.ceca.2011.03.010. View

12.

Kingma S, Wagemans T, Ijlst L, Bronckers A, van Kuppevelt T, Everts V . Altered interaction and distribution of glycosaminoglycans and growth factors in mucopolysaccharidosis type I bone disease. Bone. 2016; 88:92-100. DOI: 10.1016/j.bone.2016.01.029. View

13.

Bendor J, Logan T, Edwards R . The function of α-synuclein. Neuron. 2013; 79(6):1044-66. PMC: 3866954. DOI: 10.1016/j.neuron.2013.09.004. View

14.

Filippon L, Vanzin C, Biancini G, Pereira I, Manfredini V, Sitta A . Oxidative stress in patients with mucopolysaccharidosis type II before and during enzyme replacement therapy. Mol Genet Metab. 2011; 103(2):121-7. DOI: 10.1016/j.ymgme.2011.02.016. View

15.

Ryazantsev S, Yu W, Zhao H, Neufeld E, Ohmi K . Lysosomal accumulation of SCMAS (subunit c of mitochondrial ATP synthase) in neurons of the mouse model of mucopolysaccharidosis III B. Mol Genet Metab. 2006; 90(4):393-401. PMC: 1892176. DOI: 10.1016/j.ymgme.2006.11.006. View

16.

Holley R, Ellison S, Fil D, OLeary C, McDermott J, Senthivel N . Macrophage enzyme and reduced inflammation drive brain correction of mucopolysaccharidosis IIIB by stem cell gene therapy. Brain. 2017; 141(1):99-116. DOI: 10.1093/brain/awx311. View

17.

Fiorenza M, Moro E, Erickson R . The pathogenesis of lysosomal storage disorders: beyond the engorgement of lysosomes to abnormal development and neuroinflammation. Hum Mol Genet. 2018; 27(R2):R119-R129. DOI: 10.1093/hmg/ddy155. View

18.

Lieberman A, Puertollano R, Raben N, Slaugenhaupt S, Walkley S, Ballabio A . Autophagy in lysosomal storage disorders. Autophagy. 2012; 8(5):719-30. PMC: 3378416. DOI: 10.4161/auto.19469. View

19.

Parente M, Rozen R, Cearley C, Wolfe J . Dysregulation of gene expression in a lysosomal storage disease varies between brain regions implicating unexpected mechanisms of neuropathology. PLoS One. 2012; 7(3):e32419. PMC: 3293807. DOI: 10.1371/journal.pone.0032419. View

20.

Trudel S, Trecherel E, Gomila C, Peltier M, Aubignat M, Gubler B . Oxidative stress is independent of inflammation in the neurodegenerative Sanfilippo syndrome type B. J Neurosci Res. 2014; 93(3):424-32. DOI: 10.1002/jnr.23497. View