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Exploring Lysosomal dysfunction in Neuronal Ceroid Lipofuscinosis 

Investigador: Maria do Carmo Macário
Instituição: CHUC / CNC, Coimbra



The loss of progranulin (PGRN) expression has been directly linked with neurodegeneration in the form of neuronal ceroid lipofuscinosis 11 (NCL11), a lysosomal storage disease observed in homozygous GRN mutation carriers, or frontotemporal lobar degeneration (FTLD), an early-onset dementia present in individuals with heterozygous mutations in this gene. We recently identified a NCL11 patient bearing a homozygous GRN mutation which is one of three described cases in the world and the first one identified as a member of a family with several cases of FTLD with genetic and neuropathological confirmation. Despite recent efforts, it is still unclear how alterations in PGRN levels contribute to neuronal loss in this two pathologies, which have completely different phenotypes.

Evidences collected from PGRN deficient mice point towards a strong relation between PGRN levels and microglia and macrophage-mediated immune response, suggesting that PGRN loss may lead to exacerbated mononuclear phagocyte activation, which impairs phagocytosis and promotes the expression of proinflammatory mediators. Moreover, PGRN deficiency has also been associated with a disruption of the autophagy-lysosomal pathway. It is believed that all these molecular changes can potentiate neuroinflammation and impair degradation pathways crucial for cellular homeostasis, contributing to lipofuscin accumulation and neuronal death in NCL11.

In this study, we aim to clarify the role of PGRN in microglia and macrophage function, in the context of disease. For this purpose, and to overcome the translational limitations associated with mouse models, we propose to establish macrophage and microglia-like cultures from our NCL11 patient bearing a homozygous GRN mutation and from heterozygous GRN mutation carriers, with or without FTLD diagnosis. Using these cell models we will be able to investigate the contribution of PGRN to several events crucial for a successful innate immune response, in a dose-dependent manner. We will examine the impact of complete or partial loss of PGRN expression in two cellular pathways that culminate in the lysosome - phagocytosis and autophagy - and we will also look in detail into lysosomal biogenesis and function. Finally, we will study the impact PGRN loss in other innate immune response pathways, including the expression of pro- and anti-inflammatory mediators and on the overall activation phenotype of these cells. We strongly believe that the knowledge generated from these studies will contribute to a better understanding of NCL11 and FTLD pathogenesis and may inspire new therapeutic strategies for these diseases.

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