Abstract
Frontotemporal dementia (FTD) is a common dementia syndrome in patients under the age of 65 years with many features overlapping with amyotrophic lateral sclerosis (ALS). The link between FTD and ALS has been strengthened by the discovery that a hexanucleotide repeat expansion in a non-coding region of the C9ORF72 gene causes both familial and sporadic types of these two diseases. As we begin to understand the pathophysiological mechanisms by which this mutation leads to FTD and ALS (c9FTD/ALS), new targets for disease-modifying therapies will likely be unveiled. Putative C9ORF72 expansion pathogenic mechanisms include loss of C9ORF72 protein function, sequestration of nucleic acid binding proteins due to expanded hexanucleotide repeats, or a combination of the two. New animal models and other research tools informed by work in other repeat expansion neurodegenerative diseases such as the spinocerebellar ataxias will help to elucidate the mechanisms of C9ORF72-mediated disease. Similarly, re-examining previous studies of drugs developed to treat ALS in light of this new mutation may identify novel FTD treatments. Ultimately, research consortiums incorporating animal models and well-characterized clinical populations will be necessary to fully understand the natural history of the c9FTD/ALS clinical phenotypes and identify biomarkers and therapeutic agents that can cure the most common form of genetically determined FTD and ALS.
Highlights
Genetic forms of frontotemporal dementia and amyotrophic lateral sclerosis Frontotemporal dementia (FTD) is a common dementia in people aged under 65 years [1,2] characterized by impaired social comportment, apathy, lack of empathy, cognitive decline, and appetite changes with neuropathologic and genetic features overlapping with amyotrophic
The link between various inherited neurodegenerative diseases like fragile X-associated tremor/ataxia syndrome (FXTAS), myotonic dystrophy (DM1), spinocerebellar ataxias, and FTD is becoming stronger as more is learned about the pathogenic mechanisms of nucleotide expansion repeat diseases
A possible common mechanism for all frontotemporal lobar degeneration (FTLD)-TAR DNA binding protein (TDP) diseases involving RNA processing abnormalities could facilitate the identification of novel therapeutic agents
Summary
Genetic forms of frontotemporal dementia and amyotrophic lateral sclerosis Frontotemporal dementia (FTD) is a common dementia in people aged under 65 years [1,2] characterized by impaired social comportment, apathy, lack of empathy, cognitive decline, and appetite changes with neuropathologic and genetic features overlapping with amyotrophic. RNA antisense oligonucleotides have been studied in DM1 [41,42], were tolerated in a phase I clinical trial for SOD1-related ALS, and could be applied in c9FTD/ALS These oligonucleotides could act to interrupt sequestration of critical proteins by toxic RNA hexanucleotide repeat expansions or potentially alter the transcription or splicing of C9ORF72. TMEM106B could be a target for new therapies for patients with GRN mutations, and genes that modify C9ORF72 protein levels or function would be good targets for drugs in C9ORF72 mutation carriers Studies such as COHORT-HD (Cooperative Huntington’s Observational Research Trial) that seek to identify genetic and environmental factors that modify disease progression are being pursued in other repeat expansion diseases such as Huntington’s disease [60] and suggest that similar efforts should be pursued in c9FTD/ALS. Once biomarkers that capture C9ORF72 disease progression are developed (one possibility might be cerebrospinal fluid TDP-43 measurements), similar C9ORF72 prevention clinical trials might be considered
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