Modelling C9ORF72-ALS in brain organoids

Background
ALS is a devastating neurodegenerative disease characterized by the degeneration of upper and lower motor neurons, whereby patients lose control of their voluntary muscles and eventually die due to respiratory failure. Brain imaging studies show that C9ORF72-ALS patients present broad structural changes and cortical thinning outside primary motor areas. Moreover, the presence of systemic immune deficiencies in C9orf72 knockout (KO) mouse models and microglia pathology in C9ORF72-ALS patients suggest a cell type-specific role of C9ORF72 repeat expansions in microglia. The mechanisms underlying both cortical thinning and microglia dysfunction are not known.

Methods
To fill these gaps, we developed and use brain organoid models to analyse human cortex development in C9ORF72-ALS patients and the role of microglia herein, which we have previously shown to develop innately in our brain organoid model. In the future, we intend to test whether CRISPR/Cas9 editing of patient lines rescues the cellular phenotypes that we observe. Finally, we will test experimental therapies and assess their consequences at the molecular, cellular, and functional level.

Relevance
Our research will aid in the development and assessment of curative treatments for ALS, which are currently lacking.

Team Members
Jeroen Pasterkamp
Tijana Ljubikj
Astrid van der Geest
Danielle Vonk

Financiering: Stichting ALS Nederland; Erare-3 program ‘INTEGRALS’