Adding pieces to the puzzle: finding the role for NEK1 and C21ORF2 in ALS pathogenesis

Abstract

Amyotrophic lateral sclerosis (ALS) is a neurodegenerative disease which affects motor neurons, the cells that control movement. Loss of motor neurons leads to muscle paralysis and, therefore, ALS is invariably fatal in 3 to 5 years. No cure is currently available, and much research is ongoing to understand the causes and the mechanisms of this disease. Many genes have been found to be connected with ALS. In 2016, sequencing studies led to the discovery of NEK1 and C21ORF2. Very few details are known about the role of the proteins encoded by these two genes in the cell. Both NEK1 and C21ORF2 are necessary to protect the cell’s DNA from damage and to ensure the proper function of an organelle called primary cilium. However, nothing else is described about their possible role in neurons and how mutations of these two genes lead to the development of ALS. In this thesis, we therefore investigated different aspects of NEK1 and C21ORF2 function and how these are disrupted by ALS-linked mutations, focusing on DNA damage response and primary cilia formation/function. In addition, we identified via mass-spectrometry proteins binding to NEK1 and C21ORF2, improving our understanding of these proteins. Finally, we studied the effect of a C21ORF2 ALS-linked mutation on movement in a living organisms, using zebrafish as a model. The results of these studies form a starting point to understand the contribution of these proteins to ALS and to further develop novel therapeutic strategies