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Molecular mechanisms, experimental models and therapeutic approaches in Frontotemporal Lobe Dementia (DLFT-TDP)

16th national competition for scientific and technical research

Rare diseases

Senior Researcher : Ángeles Martín Requero

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Research Centre or Institution : Centro de Investigaciones Biológicas (CSIC)


The general aim of this research project is to reveal the possible neuroprotector role of progranuline (PGRN) in the CNS and the pathogenic influence of mutations in the PGRN gene causing haploinsufficiency in the neuronal degeneration associated with frontotemporal lobar degeneration (FTLD-TDP), a rare genetic disease for which there is no cure and which has devastating results for those affected and their families. How the PGRN deficit affects the anomalous processing of TDP‑43 protein will be studied, as well as its influence on the control of the regulatory mechanisms governing cell survival and death, as possible causes of the neuronal degeneration. It is planned to use three experimental models that include neuronal cells with reduced expression of PGRN together with PGRN-deficient mice (C57BL/6-GrntrnAidi/J), as well as peripheral cells which carry a mutation that induces haploinsufficiency. The aim is to overcome the difficulty of working with post-mortem material from patients. Firstly, three lines of lymphoblastoids were created using the peripheral blood of individuals who carry an ancestral mutation in the Basque population, c.709-1G>A, patients with FTLD and family members who are not affected. The data obtained in these cell lines have shown that the PGRN deficit is accompanied by an increase in the activity of the cell cycle, as the result of an increase in the levels of CDK6 and the phosphorylation of pRb, giving rise to a fault in the regulation of G1/S. Likewise, CDK6/pRb controls cellular vulnerability to the withdrawal of serum, in such a way that this may be a new therapeutic target, as the specific inhibitors of CDK6 restore the normal response in the same way as the addition of exogenous PGRN. Further knowledge has been gained of the signalling mechanisms altered by PGRN deficit, and important activation has been detected in the non-canonical route of Wnt5a, which is able to increase the activity of ERK1/2 through changes in Calmoduline Kinase II and PKC. It is thought that these lymphoblastic lines in FTLD patient may be used as a platform to evaluate the efficacy of certain drugs at a preclinical level. This refers to the inhibitors of CDKs such as sodium butyrate or PD0332991, as well as drugs able to increase the expression of PGRN and modulators of cell signalling.

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