The neuropathology of frontotemporal dementia and amyotrophic lateral sclerosis with a C9ORF72 hexanucleotide repeat expansion

摘要

Frontotemporal dementia (FTD) and amyotrophic lateral sclerosis (ALS) are two debilitating and relatively common early-onset neurodegenerative disorders along a clinicopathologic spectrum. Accounting for ~25% of familial FTD and ~30% of familial ALS, a GGGGCC hexanucleotide repeat expansion in chromosome 9 open reading-frame 72 (C9ORF72) is the most common known genetic cause of both disorders (c9FTD/ALS). While many neuropathologic features of c9FTD/ALS cases mirror archetypal FTD/ALS [i.e., focal neuronal loss, TAR DNA-binding protein 43 (TDP-43) pathology, etc.], a subset of neuronal lesions have been observed which are positive for ubiquitin, but negative for TDP-43, suggesting additional underlying pathology. Our goal of this study was to eliminate the possibility of the involvement other classic neurodegenerative protein (tau and amyloid-beta) and identify novel aggregating proteins which could potentially serve as biomarkers and therapeutic targets. Using quantitative neuropathologic assessment, we demonstrated tau and amyloid-beta did not consistently co-localize with these ubiquitinated inclusions and was not more common in c9FTD/ALS compared to sporadic FTD and ALS cases (as well as FTD cases with another known mutation, GRN). Following insights from the field of trinucleotide repeat disorders, we discovered novel pathologic dipeptide repeats in c9FTD/ALS generated through the process of repeat-associated non-ATG (RAN) translation. These dipeptide repeat proteins had a very characteristic and consistent morphology, distribution, and pathologic burden amongst c9FTD/ALS cases. These proteins were also highly specific to C9ORF72 repeat expansion carriers, even in clinically and neuropathologically atypical cases. Subsequent research from this initial finding has not only confirmed our results, but also demonstrated the toxicity of these proteins and even their therapeutic potential towards ameliorating disease in individuals harboring the C9ORF72 expansion.