Qiudong Deng, Termpanit Chalermpalanupap and Thomas Kukar Pages 28 - 40 ( 13 )
Increasing evidence supports the idea that frontotemporal dementia (FTD) and amyotrophic lateral sclerosis (ALS) share underlying causes and lie on opposite ends of a disease spectrum that leads to these disorders. The discovery of two different RNA binding proteins, TDP-43 and FUS/TLS, as common neuronal inclusions in FTD and ALS patients has strengthened this connection. Subsequent identification of mutations in TDP-43 and FUS that cause ALS, and FTD in rare cases, provides additional linkage between these diseases. Furthermore, autosomal dominant forms of FTD, ALS, or a combined phenotype can occur in the same family. Genetic studies have linked some of these cases to chromosome 9p21 and are known as c9FTD/ALS. Recently, an expanded GGGGCC hexanucleotide repeat in the C9ORF72 gene has been identified in c9FTD/ALS cases as well as sporadic forms of both diseases. Preliminary data suggest that the increased nucleotide repeats in C9ORF72 lead to RNA inclusions or foci in the nucleus of affected cells. Analogous to other repeat disorders such as myotonic dystrophy, expanded repeats in C9ORF72 may cause disease pathogenesis by sequestering RNA binding proteins and/or perturbing the splicing and regulation of key proteins regulating neuronal health and survival. Intriguingly, TDP-43 and FUS/TLS play fundamental roles in RNA regulation and splicing, and their mutation leads to dysfunctional regulation of their targets in model systems. Finally, defects in RNA splicing have been reported in sporadic ALS and a number of other genes involved in RNA metabolism (ANG, SETX, TAF15, ELP3, ATXN2) are associated with ALS. Based on these recent findings, we propose that defects in RNA metabolism are a common pathway linking FTD and ALS, and are responsible for disease pathogenesis in a significant portion of cases. Further research to test this hypothesis and determine if these proteins function within common biological pathways and share similar pathogenic mechanisms will ultimately open up new routes of therapy for these devastating disorders.
AD, ALS, FTD, FTLD, FUS, TLS, C9ORF72, PD, TDP-43, proteinopathies, neurodegeneration, inclusion.
Emory University, School of Medicine, Department of Pharmacology, 1510 Clifton Rd NE, 5123 Rollins Research Center, Atlanta, GA 3032 2-3090.