Interactie tussen Progranuline en TDP-43 in de pathogenese van Amyotrofe Lateraal Sclerose

Amyotrophic Lateral Sclerosis (ALS) and Frontotemporal Lobar Degeneration (FTLD) are two related neurodegenerative disorders, representing the ends of a disease spectrum, with many intermediate forms in between. Not only clinically, but also at the genetic and pathological level, there is growing evidence for an overlap. TDP-43 has a central position in the pathogenesis: TDP-43 pathology is found in more than 95% of ALS patients (both in patients with and without mutations in the gene encoding TDP-43) and in about 40% of FTLD patients, in whom mutations in progranulin (PGRN), leading to haploinsufficiency, are commonly found. Since PGRN is known to be a neurotrophic factor and can rescue the mutant TDP-43 induced (but not the mutant SOD1 induced) axonopathy in zebrafish, we investigated the therapeutic potential of PGRN in rodent models for ALS. To this end, mutant SOD1 and TDP-43 mice were crossbred with human PGRN overexpressing mice and mutant SOD1 and TDP-43 rats were implanted with intracerebroventricular catheters connected to mini-osmotic pumps with hPGRN. However, since all existing TDP-43 mouse models have their limitations, we first aimed to characterize and optimize the most widely used TDP-43 mouse: the Prnp mutant human TDP-43 (A315T) mouse. The use of this mouse is currently hampered by sudden death, due to intestinal pseudo-obstruction. By feeding these mice a jellified fiber deprived food, the sudden death was abolished, disease duration significantly extended up to several months, and a progressive degeneration of upper and lower motor axons became apparent. In line with the results in zebrafish, we could not detect a beneficial effect of PGRN in mutant SOD1 mice and rats. But, PGRN increased survival of a sub group of TDP-43 mice, in particular the mice with a slow disease progression. In addition, preliminary results showed that PGRN overexpression reduced the Lcn2 expression, which is increased in TDP-43 mice. Lcn2 is a neurotoxic factor, released by astrocytes. These observations open new avenues for research into the role of PGRN in Lcn2 production and toxicity, and will hopefully lead to the identification of novel therapeutic targets for ALS (and FTLD) patients with TDP-43 pathology.status: publishe