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- The Biology of Lysosomes: From Order to DisorderPublication . Amaral, Olga; Martins, Mariana; Oliveira, Ana Rita; Duarte, Ana Joana; Mondragão-Rodrigues, Inês; Macedo, M. FatimaSince its discovery in 1955, the understanding of the lysosome has continuously increased. Once considered a mere waste removal system, the lysosome is now recognised as a highly crucial cellular component for signalling and energy metabolism. This notable evolution raises the need for a summarized review of the lysosome’s biology. As such, throughout this article, we will be compiling the current knowledge regarding the lysosome’s biogenesis and functions. The comprehension of this organelle’s inner mechanisms is crucial to perceive how its impairment can give rise to lysosomal disease (LD). In this review, we highlight some examples of LD fine-tuned mechanisms that are already established, as well as others, which are still under investigation. Even though the understanding of the lysosome and its pathologies has expanded through the years, some of its intrinsic molecular aspects remain unknown. In order to illustrate the complexity of the lysosomal diseases we provide a few examples that have challenged the established single gene—single genetic disorder model. As such, we believe there is a strong need for further investigation of the exact abnormalities in the pathological pathways in lysosomal disease.
- Can enzyme replacement therapy revert¨iNKT¨cell dysfunction in acid sphingomyelinase deficiency patients?Publication . Chaves, João; da Silva Gaspar, Paulo Jorge Miranda; Macedo, FatimaAcid sphingomyelinase deficiency (ASMD) is a lysosomal storage disease caused by deficient activity of the enzyme acid sphingomyelinase (ASM), resulting in an abnormal accumulation of sphingomyelin in lysosomes. The abnormal accumulation of sphingomyelin, a crucial cell membrane component, ultimately impairs pulmonary, hepatic, and sometimes neurological functions, with severe forms of the disease being fatal in the first years of life. Invariant Natural Killer T (iNKT) cells are lipid-reactive T cells that play a central role in a wide range of immune responses including cancer, infection and inflammation. iNKT cells are restricted to CD1d, depending on the presentation of lipids by this molecule for their function. Sphingomyelin is a lipid with affinity for CD1d and its accumulation in ASMD influences the role of iNKT cells by impairing normal lipid antigen presentation to these cells. Interestingly, ASM-/- mice have reduced number of iNKT cells and impaired iNKT cell activity, in ASMD patients a reduced frequency of iNKT cells is also observed (1). Noteworthy, enzyme replacement therapy (ERT) with recombinant ASM can prevent iNKT cell deficiency in ASM-/- mice (1). In the current study we are investigating the effect of ERT on iNKT cells in ASMD adult patients.
- Olipudase alfa enzyme replacement therapy. One-year outcomes in an adult patient with acid sphingomyelinase deficiency type BPublication . Cardoso, M.; Chaves, P.C.; Pintalhão, M.; da Silva Gaspar, Paulo Jorge Miranda; Castro, R.; Bastos, J.; Silva, A.; Campos, T.; Macedo, Fatima; Rodrigues, E.; Leão Teles, ElisaIntroduction: Acid Sphingomyelinase Deficiency (ASMD) is a rare autosomal recessive lysosomal storage disorder caused by variants in the SMPD1 gene, leading to a deficiency in the activity of sphingomyelinase (ASM) that catabolizes sphingomyelin (SPM). ASMD Type B is a late-onset, severe disease characterized by progressive hepatosplenomegaly, gradual deterioration of liver and pulmonary function, osteopenia and an atherogenic lipid profile. Olipudase alfa is a recombinant human ASM enzyme replacement therapy indicated for the treatment of non-C-NS manifestations of ASMD.