Repeat length increases disease penetrance and severity in C9orf72 ALS/FTD BAC transgenic mice

Abstract

C9orf72 ALS/FTD patients show remarkable clinical heterogeneity, but the complex biology of the repeat expansion mutation has limited our understanding of the disease.BAC transgenic mice were used to better understand the molecular mechanisms and repeat length effects of C9orf72 ALS/FTD. Genetic analyses of these mice demonstrate that the BAC transgene and not integration site effects cause ALS/FTD phenotypes.Transcriptomic changes in cell proliferation, inflammation and neuronal pathways are found late in disease and alternative splicing changes provide early molecular markers that worsen with disease progression. Isogenic sublines of mice with 800, 500 or 50 G4C2 repeats generated from the single-copy C9-500 line show longer repeats result in earlier onset, increased disease penetrance, and increased levels of RNA foci and RAN aggregates. These data demonstrate G4C2 repeat length is an important driver of disease and identify alternative splicing changes as early biomarkers of C9orf72 ALS/FTD.

Rare and common variant analyses of amyotrophic lateral sclerosis in the French-Canadian genome

“…Currently it is difficult to assess large C9orf72 expansion lengths, even with advancements in sequencing technology 29 . It is indeed likely that larger repeat lengths are more deleterious and penetrant than smaller lengths 30,31 , and future studies with accurate sizing data could evaluate the association between ALS PRS and C9orf72 expansion length.…”

CCG•CGG interruptions in high‐penetrance SCA8 families increase RAN translation and protein toxicity

“…There is a growing body of evidence that structured RNAs, including RNA hairpins, favor efficient RAN translation (Zu et al , 2011; Banez‐Coronel et al , 2015; Wang et al , 2019). RAN translation has also been shown to be more efficient with longer repeat lengths, and longer repeats increase the stability of RNA secondary structures (Napierala et al , 2005; Zu et al , 2011, 2013; Banez‐Coronel et al , 2015; Wang et al , 2019; Pattamatta et al , 2020). Our data extend these results and show that CGG interruptions, which increase the stability of RNA hairpins, also lead to elevated levels of RAN proteins and show that increasing RNA stability without altering repeat tract length increases RAN translation.…”