ALS Genes in the Genomic Era and their Implications for FTD Hung Phuoc Nguyen, Christine Van Broeckhoven, Julie van der Zee  Trends in Genetics  Volume 34, Issue 6, Pages 404-423 (June 2018) DOI: 10.1016/j.tig.2018.03.001 Copyright © 2018 The Authors Terms and Conditions

Figure 1 Key Figure: Inferred Key Molecular Mechanisms in ALS-FTD Spectrum Pathology. (A) Mutations in TBK1, OPTN, SQSTM1 (p62), UBQLN2, VCP, and CCNF impair protein degradation by affecting the UPS and autophagy pathways. Annexin A11 is involved in vesicular trafficking between the Golgi and ER. Through its binding with calcyclin (S10036) it regulates proteostasis. Mutant annexin A11 aggregates and also sequesters wild type protein, possibly resulting in defective proteostasis and, in turn, TDP-43 accumulation. (B) Disturbances in RNA processing result from mutations in TARDBP, FUS, MATR3, TIA1, hnRNPA1, hnRNA2B1, and C9orf72. Cytoplasmic aggregation of TDP-43 and FUS are common pathological hallmarks in both ALS and FTD. (C) Identification of CHCHD10 mutations has underscored the role of mitochondrial dysfunction in ALS. (D) Similar to TARDBP and FUS, NEK1, C21orf2, and C9orf72 are also associated with impaired DNA damage response. (E) Like PFN1, mutations in TUBA4A alter cytoskeleton dynamics, which affects microtubule integrity and axonal transport; this is also likely for TDP-43. The red stars represent mutated proteins. Abbreviations: ALS, amyotrophic lateral sclerosis; DPR, dipeptide repeat aggregates; ER, endoplasmic reticulum; FTD, frontotemporal dementia; RAN, repeat-associated non-AUG translation; UPS, ubiquitin-proteasome system. Trends in Genetics 2018 34, 404-423DOI: (10.1016/j.tig.2018.03.001) Copyright © 2018 The Authors Terms and Conditions