Comparative interactomics analysis of different ALS-associated proteins identifies converging molecular pathways

• DOI: 10.1007/s00401-016-1575-8
• Publication Date: 2016-05-10T18:20:33Z
• Authors: Anna M. Blokhuis; Max Koppers; Ewout J. N. Groen; Dianne M. A. van ...; Stefano Dini Modi...; Jasper J. Anink; Katsumi Fumoto; Femke van Diggelen; Anne Snelting; Peter Sodaar; Bert M. Verheijen; Jeroen A. A. Demmers; Jan H. Veldink; Eleonora Aronica; Irene Bozzoni; Jeroen den Hertog; Leonard H. van de...; R. Jeroen Pasterkamp
• Keywords: C9ORF72

Amyotrophic lateral sclerosis (ALS) is a devastating neurological disease with no effective treatment available. An increasing number of genetic causes ALS are being identified, but how these defects lead to motor neuron degeneration and which extent they affect common cellular pathways remains incompletely understood. To address questions, we performed an interactomic analysis identify binding partners wild-type (WT) ALS-associated mutant versions ATXN2, C9orf72, FUS, OPTN, TDP-43 UBQLN2 in neuronal cells. This identified several known also many novel proteins. Interactomes WT proteins were very similar except for OPTN UBQLN2, mutations caused loss or gain protein interactions. Several the interactomes showed high degree overlap: shared FUS had roles RNA metabolism; OPTN- UBQLN2-interacting related degradation transport, C9orf72 interactors function mitochondria. confirm that this overlap important pathogenesis, studied fragile X mental retardation (FMRP), one TDP-43, more detail vitro vivo model systems ALS. FMRP localized FUS-containing aggregates spinal neurons bound endogenous direct RNA-sensitive manner. Furthermore, synaptic mRNA target expression, neuromuscular junction integrity, behavior by zebrafish embryos, could be rescued exogenous expression. Together, results show interactomics can provide crucial insight into mechanisms link dysfunction mutations.