The essential and downstream common proteins of amyotrophic lateral sclerosis: A protein-protein interaction network analysis

Abstract

Amyotrophic Lateral Sclerosis (ALS) is a devastative neurodegenerative disease characterized by selective loss of motoneurons. While several breakthroughs have been made in identifying ALS genetic defects, the detailed molecular mechanisms are still unclear. These genetic defects involve in numerous biological processes, which converge to a common destiny: motoneuron degeneration. In addition, the common comorbid Frontotemporal Dementia (FTD) further complicates the investigation of ALS etiology. In this study, we aimed to explore the protein-protein interaction network built on known ALS-causative genes to identify essential proteins and common downstream proteins between classical ALS and ALS+FTD (classical ALS + ALS/FTD) groups. The results suggest that classical ALS and ALS+FTD share similar essential protein set (VCP, FUS, TDP-43 and hnRNPA1) but have distinctive functional enrichment profiles. Thus, disruptions to these essential proteins might cause motoneuron susceptible to cellular stresses and eventually vulnerable to proteinopathies. Moreover, we identified a common downstream protein, ubiquitin-C, extensively interconnected with ALS-causative proteins (22 out of 24) which was not linked to ALS previously. Our in silico approach provides the computational background for identifying ALS therapeutic targets, and points out the potential downstream common ground of ALS-causative mutations.

Fig 1. Overall work flow.

Fig 2

The clusters of (a) classical ALS, 136 clusters at k = 4; (b) ALS+FTD, 59 clusters at k = 5. The yellow highlights the core clusters identified by significant involvement ranking calculated in Table 3 based on Thompson Tau test.

Fig 3

Essential proteins ranked by HC (a) classical ALS; (b) ALS+FTD. ** >mean ±τ SD; * >mean ±(τ SD)/2

Fig 4. Profiles of the interacting proteins.

A) Profile of C9orf72 with only direct interaction B) The profiles include both direct and indirect interactions of important downstream proteins. Red, blue and green denote direct, secondary and tertiary contact proteins respectively. Yellow highlights ALS/FTD proteins.