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Molecular analyses of genes involved in mannose 6-phosphate independent trafficking

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dc.contributor.authorCoutinho, Maria Francisca
dc.contributor.authorLacerda, Lúcia
dc.contributor.authorPinto, Eugénia
dc.contributor.authorRibeiro, Helena
dc.contributor.authorPrata, Maria João
dc.contributor.authorAlves, Sandra
dc.date.accessioned2014-03-17T13:18:01Z
dc.date.available2014-03-17T13:18:01Z
dc.date.issued2013-09
dc.description.abstractLysosomes are essential regulators of cell homeostasis, since they harbour a vast repertory of specialized enzymes responsible for degrading endocytosed and intracellular material. The newly-synthesized lysosomal enzymes travel first to the trans-Golgi network (TGN) and then must be driven to the acidic organelle in order to exert their function. Whist the best-known pathway for TGN-to-endosome transport is the delivery of soluble lysosomal hydrolases by the MPRs, additional pathways from the TGN to lysosomes do exist, as recently demonstrated by the identification of two alternative receptors: LIMP-2, shown to be implicated in the delivery of -glucocerebrosidase to the lysosomes, and sortilin, proposed to be involved in the transport of several proteins including the sphingolipid activator proteins prosaposin and GM2 activator protein (GM2AP), acid sphingomyelinase (ASM) and cathepsins D and H. Disruption of the intracellular transport and delivery pathways to the lysosomes may result in lysosomal dysfunction, predictably leading to a range of clinical manifestations suggestive of lysosomal storage diseases (LSDs): impairments of the M6P-dependent pathway are the basis of the rare genetic diseases Mucolipidosis II and III (ML II, OMIM# 252500 and ML III, OMIM# 252600); similarly, impairments on the M6P-independent trafficking processes might also have hazardous effects to the organism, ultimately leading to overt disease as already demonstrated by the existence of a serious autosomal-recessive disorder presently known as action myoclonus-renal failure syndrome (AMRF), which is caused by mutations in the gene that codes for LIMP-2. Having in mind that, for a great percentage of patients presenting LSD manifestations, no condition is successfully diagnosed because their metabolic profile does not fit any known LS, we hypothesized that TGN-to-endosome M6P-independent traffic could be deficient in some of them. For the present study we recruited uncharacterized patients with phenotypes overlapping manifestations that could predictably be due to loss of activities of GCase, saposins, GM2AP and/or ASM, to find out whether those features could be resultant from failures in M6P-independent pathways through which those proteins reach the lysosome. Patients were sorted into five different groups according to their phenotypic picture and screened for SCARB2 and/or SORT1 mutations. No novel mutations were found on the SCARB2 gene and no pathogenic mutations were identified on the SORT1 gene. Other study approaches will be needed to clarify whether sortilin dysfunction may cause disease. The relevance of alternative receptors is demonstrated by their involvement in disease. So, a better understanding on the M6P-independent routes to the lysosome will contribute to a more accurate understanding not only of crucial cellular processes, but also of the pathophysiological bases of severe and disabling diseases. Finally, knowledge of the different trafficking mechanisms responsible for the sorting of lysosomal proteins may be an enormous help for the building of new therapeutic strategies for LSDs.por
dc.identifier.urihttp://hdl.handle.net/10400.18/2149
dc.language.isoengpor
dc.relationFCT – PTDC/SAU-GMG/102889/2008por
dc.subjectDoenças Genéticaspor
dc.subjectSCARB2por
dc.subjectSORT1por
dc.subjectMannose 6-phosphate independent Traffickingpor
dc.titleMolecular analyses of genes involved in mannose 6-phosphate independent traffickingpor
dc.typeconference object
dspace.entity.typePublication
oaire.citation.conferencePlaceGraz, Austriapor
oaire.citation.title19th ESGLD Workshop (European Study Group on Lysosomal Diseases), 26-29 September 2013por
rcaap.rightsrestrictedAccesspor
rcaap.typeconferenceObjectpor

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