Poly(GR) in C9ORF72 -Related ALS/FTD Compromises Mitochondrial Function and Increases Oxidative Stress and DNA Damage in iPSC-Derived Motor Neurons

Abstract

SUMMARY GGGGCC repeat expansions in C9ORF72 are the most common genetic cause of both ALS and FTD. To uncover underlying pathogenic mechanisms, we found DNA damage was greater, in an age-dependent manner, in motor neurons differentiated from iPSCs of multiple C9ORF72 patients than control neurons. Ectopic expression of the dipeptide repeat (DPR) protein (GR)80 in iPSC-derived control neurons increased DNA damage, suggesting poly(GR) contributes to DNA damage in aged C9ORF72 neurons. Oxidative stress was also increased in C9ORF72 neurons in an age-dependent manner. Pharmacological or genetic reduction of oxidative stress partially rescued DNA damage in C9ORF72 neurons and control neurons expressing (GR)80 or (GR)80-induced cellular toxicity in flies. Moreover, interactome analysis revealed that (GR)80 preferentially bound to mitochondrial ribosomal proteins and caused mitochondrial dysfunction. Thus, poly(GR) in C9ORF72 neurons compromises mitochondrial function and causes DNA damage in part by increasing oxidative stress, revealing another pathogenic mechanism in C9ORF72-related ALS and FTD.

Converging Mechanisms of p53 Activation Drive Motor Neuron Degeneration in Spinal Muscular Atrophy

“…In addition to SMA motor neurons (this study), accumulation of phospho-p53 S15 has been documented in human stem cell-derived motor neurons from C9ORF72-related ALS patients (Lopez-Gonzalez et al, 2016) and that of phospho-p53 S18 in neonatal axotomized mouse motor neurons (Martin and Wong, 2017). However, the functional relevance of this specific modification for the neurodegenerative process was not previously investigated in any disease models.…”

RNA-binding proteins in neurodegeneration: mechanisms in aggregate

“…Meanwhile, more informative visualization of foci in post-mortem human tissue is fraught with preservation, fixation, and background technicalities. While toxicity of DPRs has been shown in model organisms and cell culture (Wen et al 2014;Lopez-Gonzalez et al 2016), this could reflect nonphysiological effects resulting from overexpression. Understanding how DPRs are made (Green et al 2016) and how abundant they truly are in degenerating regions (Gomez-Deza et al 2015) will be important in order to gauge how critical they are to the pathology of the ALS/FTD spectrum.…”

SIRT1 deacetylase in aging‐induced neuromuscular degeneration and amyotrophic lateral sclerosis

“…Several targets of SIRT1 including PGC‐1α and FoxO1/3 have been previously shown to influence mitochondrial biogenesis, antioxidant formation, and inflammation (Brunet, 2004; Lagouge et al, 2006). These findings are interesting because mitochondrial dysfunction and the formation of reactive oxygen species are thought to occur in SOD1 mutation carriers as well as patients with C9ORF72 mutations, mutant TDP43, and FUS during ALS pathogenesis (Lopez‐Gonzalez et al, 2016; Onesto et al, 2016). …”