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Author: Dieter Edbauer2
Multiomic ALS signatures highlight subclusters and sex differences suggesting the MAPK pathway as therapeutic target.

Abstract (Expand)

Amyotrophic lateral sclerosis (ALS) is a debilitating motor neuron disease and lacks effective disease-modifying treatments. This study utilizes a comprehensive multiomic approach to investigate the … early and sex-specific molecular mechanisms underlying ALS. By analyzing the prefrontal cortex of 51 patients with sporadic ALS and 50 control subjects, alongside four transgenic mouse models (C9orf72-, SOD1-, TDP-43-, and FUS-ALS), we have uncovered significant molecular alterations associated with the disease. Here, we show that males exhibit more pronounced changes in molecular pathways compared to females. Our integrated analysis of transcriptomes, (phospho)proteomes, and miRNAomes also identified distinct ALS subclusters in humans, characterized by variations in immune response, extracellular matrix composition, mitochondrial function, and RNA processing. The molecular signatures of human subclusters were reflected in specific mouse models. Our study highlighted the mitogen-activated protein kinase (MAPK) pathway as an early disease mechanism. We further demonstrate that trametinib, a MAPK inhibitor, has potential therapeutic benefits in vitro and in vivo, particularly in females, suggesting a direction for developing targeted ALS treatments.

Authors: Lucas Caldi Gomes, Sonja Hänzelmann, Fabian Hausmann, Robin Khatri, Sergio Oller, Mojan Parvaz, Laura Tzeplaeff, Laura Pasetto, Marie Gebelin, Melanie Ebbing, Constantin Holzapfel, Stefano Fabrizio Columbro, Serena Scozzari, Johanna Knöferle, Isabell Cordts, Antonia F Demleitner, Marcus Deschauer, Claudia Dufke, Marc Sturm, Qihui Zhou, Pavol Zelina, Emma Sudria-Lopez, Tobias B Haack, Sebastian Streb, Magdalena Kuzma-Kozakiewicz, Dieter Edbauer, R Jeroen Pasterkamp, Endre Laczko, Hubert Rehrauer, Ralph Schlapbach, Christine Carapito, Valentina Bonetto, Stefan Bonn, Paul Lingor

Date Published: 1st Jul 2024

Publication Type: Journal

Peripheral expression of brain-penetrant progranulin rescues pathologies in mouse models of frontotemporal lobar degeneration.

Abstract (Expand)

Progranulin (PGRN) haploinsufficiency is a major risk factor for frontotemporal lobar degeneration with TAR DNA-binding protein 43 (TDP-43) pathology (FTLD-<i>GRN</i>). Multiple therapeutic … strategies are in clinical development to restore PGRN in the CNS, including gene therapy. However, a limitation of current gene therapy approaches aimed to alleviate FTLD-associated pathologies may be their inefficient brain exposure and biodistribution. We therefore developed an adeno-associated virus (AAV) targeting the liver (L) to achieve sustained peripheral expression of a transferrin receptor (TfR) binding, brain-penetrant (b) PGRN variant [AAV(L):bPGRN] in two mouse models of FTLD-<i>GRN</i>, namely, <i>Grn</i> knockout and <i>GrnxTmem106b</i> double knockout mice. This therapeutic strategy avoids potential safety and biodistribution issues of CNS-administered AAVs and maintains sustained concentrations of PGRN in the brain after a single dose. AAV(L):bPGRN treatment reduced several FTLD-<i>GRN</i>-associated pathologies including severe motor function deficits, aberrant TDP-43 phosphorylation, dysfunctional protein degradation, lipid metabolism, gliosis, and neurodegeneration in the brain. The potential translatability of our findings was tested in an in vitro model using cocultured human induced pluripotent stem cell (hiPSC)-derived microglia lacking PGRN and TMEM106B and wild-type hiPSC-derived neurons. As in mice, aberrant TDP-43, lysosomal dysfunction, and neuronal loss were ameliorated after treatment with exogenous TfR-binding protein transport vehicle fused to PGRN (PTV:PGRN). Together, our studies suggest that peripherally administered brain-penetrant PGRN replacement strategies ameliorate FTLD-<i>GRN</i> relevant phenotypes including TDP-43 pathology, neurodegeneration, and behavioral deficits. Our data provide preclinical proof of concept for the use of this AAV platform for treatment of FTLD-<i>GRN</i> and potentially other CNS disorders.

Authors: Marvin Reich, Matthew J Simon, Beate Polke, Iñaki Paris, Georg Werner, Christian Schrader, Lena Spieth, Sonnet S Davis, Sophie Robinson, Gabrielly Lunkes de Melo, Lennart Schlaphoff, Katrin Buschmann, Stefan Berghoff, Todd Logan, Brigitte Nuscher, Lis de Weerd, Dieter Edbauer, Mikael Simons, Jung H Suh, Thomas Sandmann, Mihalis S Kariolis, Sarah L DeVos, Joseph W Lewcock, Dominik Paquet, Anja Capell, Gilbert Di Paolo, Christian Haass

Date Published: 5th Jun 2024

Publication Type: Journal

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