C9orf72 Di-peptide Aggregation Assay

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C9orf72 Di-peptide Aggregation in Amyotrophic Lateral Sclerosis (ALS)

Frontotemporal lobar degeneration (FTLD) and ALS are the extreme ends of a spectrum of overlapping neurodegenerative disorders variably associated with dementia, personality changes, language abnormalities, and progressive muscle weakness. Most patients show intracellular inclusions strongly positive for phosphorylated TAR DNA-binding protein of 43kDa (TDP-43) (classified as FTLD-TDP, FTLD/ALS-TDP, or ALS-TDP). Expansion of a GGGGCC hexanucleotide repeat in the gene C9orf72 has been identified as the most common pathogenic mutation in families with autosomal dominant FTLD, FTLD/ALS, and ALS. Depending on the transcript isoform, the expansion is located upstream of the C9orf72 coding region, either in the first intron or the promoter region. Although the extreme GC-content precludes sequencing in patients, the number of GGGGCC repeat units is believed to be at least several hundred compared to fewer than 25 in healthy controls.

Fig. 1. The G₄C₂ repeat expansion can cause C9orf72 ALS/FTD through three proposed mechanisms. (Schmitz, et al., 2021)

Patients with a C9orf72 repeat expansion mutation have clinical symptoms similar to other FTLD/ALS-TDP but show several unique pathological features. Aggregates of phosphorylated TDP-43 are accompanied by abundant dot-like and star-shaped phospho-TDP-43-negative neuronal cytoplasmic inclusions in particular in the cerebellum, hippocampus, and frontotemporal neocortex that can only be identified with antibodies for p62, ubiquitin or the related ubiquilins. These phospho-TDP-43 negative aggregates are highly characteristic of diseased C9orf72 mutation carriers and are absent in other variants of FTLD/ALS-TDP. The identity of the disease protein(s) in these inclusions and their relation to the C9orf72 hexanucleotide repeat expansion has remained elusive. Neurodegenerative changes through the G4C2 repeat expansion within the C9orf72 gene involve the loss-of-function (LOF) of the C9orf72 gene due to the hexanucleotide repeat expansion. Evaluation of postmortem tissue of C9orf72 ALS/FTD patients has indicated that a significant decrease in total C9orf72 transcript levels and C9orf72 protein levels were observed compared to healthy controls. Reduction of both mRNA transcript and protein levels was also observed in iPSC-derived motor neurons from C9orf72 ALS/FTD patients, further supporting the decrease in C9orf72 level due to hexanucleotide repeat expansion.

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Reference

1. Schmitz, A.; et al. Emerging Perspectives on Dipeptide Repeat Proteins in C9orf72 ALS/FTD. Front Cell Neurosci. 2021, 15: 637548.