Genetic Convergence Brings Clarity to the Enigmatic Red Line in ALS

G4C2repeat RNA mediates the disassembly of the nuclear pore complex in C9orf72 ALS/FTD

“…It has been proposed that the C9orf72 HRE exerts toxicity through the combination of three pathological phenomena including haploinsufficiency of C9ORF72 protein, accumulation of G 4 C 2 and G 2 C 4 repeat RNA, and production of toxic DPRs (Balendra and Isaacs, 2018;Cook and Petrucelli, 2019;Gitler and Tsuiji, 2016). Although we do not observe a reduction in C9ORF72 protein in our iPSN model ( Fig.…”

“…S1A-B). Importantly, C9orf72 ALS/FTD clinically and pathologically affects multiple different populations of neurons including interneurons, upper motor neurons, and neurons within the frontal and temporal cortices across two clinically distinct but genetically overlapping neurodegenerative diseases ALS and FTD (Cook and Petrucelli, 2019;Ferrari et al, 2011). As more than just Islet-1 positive lower motor neurons are affected in disease, the analysis of all neurons within iPSC derived spinal neurons cultures is essential for a comprehensive understanding of pathogenic mechanisms.…”

Sequestration of TDP-43216-414aggregates by cytoplasmic expression of the proSAAS chaperone

“…Interestingly, the TDP-43 219-414 form, which results from caspase cleavage (Zhang et al, 2007), has a higher potential for seeding aggregation as compared to other TDP-43 proteins ( (Huang et al, 2014); see also (Nonaka and Hasegawa, 2019)). It should also be mentioned that TDP-43 deposition, while most commonly found in FTLD and ALS (reviewed in (Cook and Petrucelli, 2019)), also occurs in several other neurodegenerative diseases, including AD (reviewed in (Kovacs, 2019;Uchino et al, 2015)), hippocampal sclerosis (Kovacs et al, 2013), Lewy body disease (Nakashima-Yasuda et al, 2007)),and argyrophilic grain disease (Fujishiro et al, 2009); reviewed in (Arnold et al, 2013). Thus far no studies have investigated the potential colocalization of proSAAS with TDP-43 aggregates in tissues taken from patients with FTLD or ALS.…”

Structural Variants May Be a Source of Missing Heritability in sALS

“…Approximately 10% of ALS cases are classed as familial (fALS), while the remainder, with no prior family involvement, are classified as having the sporadic form of the disease (sALS) (Renton et al, 2014). Since the landmark discovery of the first mutation in the superoxide dismutase 1 gene (SOD1) in fALS in the early 1990s (Rosen et al, 1993), there has since been significant progress in understanding of the genetics of the familial disease, with approximately 70% of the genetic mutations that contribute to fALS having been identified (Cook and Petrucelli, 2019). However the genetic underpinnings of sporadic ALS (sALS) remain a formidable challenge (Al-Chalabi et al, 2012;Renton et al, 2014).…”