Genetic architecture and pathogenic mechanisms of ALS: Repeats, animal models and interactomics

Amyotrophic lateral sclerosis (ALS) is a neurodegenerative disease affecting motor neurons, ultimately leading to death due to respiratory failure 3-5 years after disease onset. In this doctoral thesis, the genetic etiology and pathogenic mechanisms of ALS have been studied.

To gain more insight into the genetic etiology and genetic architecture of ALS in the Netherlands, we have determined the frequency of several ALS-associated genes (ANG, VCP and VAPB) in the Dutch ALS population. Also, several studies aimed to discover new variants involved in ALS were performed. In these studies we have identified intermediate repeat expansions in the NIPA1 gene as a novel risk factor for ALS and excluded coding variants in UNC13a and C9orf72, as well as repeat expansions in FMR1, to be associated with ALS. Although in the past decades significant progress has been made on the genetic etiology of ALS, the underlying pathogenic mechanisms remain poorly understood. By characterizing newly generated knockout mice for the ALS-associated gene C9orf72, I have ruled out haploinsufficiency as the sole causative pathogenic mechanism underlying ALS. In addition, to increase our knowledge about protein function and to identify possible converging pathways in ALS, we have performed interactome analyses of six ALS-associated proteins and discovered overlapping protein-binding partners between several ALS-associated proteins OPTN and UBQLN2 and between FUS, ATXN2 and TDP-43. We further characterized the interaction between FUS and FMRP, one of the overlapping protein-binding partners of ALS-associated proteins FUS, ATXN2 and TDP-43, and discovered that FMRP could rescue FUS induced ALS pathogenesis in an in vivo model.