Genetics insight into the amyotrophic lateral sclerosis/frontotemporal dementia spectrum

Abstract

Recent genetic discoveries have dramatically changed our understanding of two major neurodegenerative conditions. Amyotrophic lateral sclerosis (ALS) and frontotemporal dementia (FTD) are common, devastating diseases of the brain. For decades, ALS and FTD were classified as movement and cognitive disorders, respectively, due to their distinct clinical phenotypes. The recent identification of chromosome 9 open reading frame 72 (C9orf72) as the major gene causative of familial forms of ALS and FTD uncovered a new reality of a continuous FTD/ALS spectrum. The finding that up to 50% of all patients present some degree of ALS and FTD phenotypes supports this ALS/FTD continuum. Now >100 genes are known to contribute to ALS/FTD, with a few major contributors that are reviewed below. The low penetrance of C9orf72 mutations, its contribution to sporadic cases, and its combination with other genes support an oligogenic model where two or more genes contribute to disease risk, onset, progression and phenotype: from 'pure' ALS or FTD to combined ALS/ FTD. These advances in the genetics of ALS/FTD will soon lead to a better mechanistic understanding of the pathobiology of the disease, which should result in the development of effective therapies in the near future.

TIA1 Mutations in Amyotrophic Lateral Sclerosis and Frontotemporal Dementia Promote Phase Separation and Alter Stress Granule Dynamics

“…While most patients present with ALS alone, a subset of individuals present with concomitant frontotemporal dementia (ALS/FTD) (Hardy and Rogaeva, 2014). Recent gene discoveries and clinicopathological studies have highlighted that ALS and FTD are part of a disease continuum with a shared genetic etiology (Ji et al, 2017; Neumann et al, 2006). Repeat expansions in the chromosome 9 open reading frame 72 gene ( C9orf72 ) and mutations in TBK1 (encoding TANK-binding kinase 1), and TARDBP (encoding transactive response DNA-binding protein 43, TDP-43) are among the most common genetic causes of the combined ALS/FTD phenotype and, notably, each of these mutations results in pathology characterized by TDP-43-positive neuronal cytoplasmic inclusions (Cirulli et al, 2015; DeJesus-Hernandez et al, 2011; Freischmidt et al, 2015; Kabashi et al, 2008; Renton et al, 2011; Sreedharan et al, 2008).…”

Etiogenic factors present in the cerebrospinal fluid from amyotrophic lateral sclerosis patients induce predominantly pro-inflammatory responses in microglia

“…In recent years, the focus has largely shifted to transgenic models with novel, gene mutations more commonly reported in ALS patients, thus narrowing the gap between animal models and actual disease etiopathogenesis. Of prominence are ubiquitinated cytoplasmic inclusions (~ 98%)/mutations (FALS 5%, SALS 1%) in 43-kDa TAR DNA-binding protein (TDP-43), fused in sarcoma (FUS) (FALS 4%, SALS < 1%) and, most prominently, the hexaneucleotide repeat expansion in C9orf72 (FALS 40%, SALS > 10%) [ 19 – 21 ]. However, while these models recapitulate the etiopathogenesis of FALS more effectively, their relevance from the perspective of SALS pathogenesis, which constitutes 90% of the ALS etiology, is still dubious [ 22 ].…”

Novel Aspects on Motor Neuron Disease: The Recent Genetic Studies on ALS

“…The cellular processes, including RNA processing, protein degradation pathways, ubiquitin-proteasome system (UPS), autophagy, and so on, are all reported related to ALS pathogenesis [1][2][3][7][8][9][10][11][12][13][14][15][16][17][18][19][20][21][22]. Sorted by the various processes, we summarize the causative genes and genes might increase susceptibility of ALS which impact physiological activities mentioned above (Figure 1).…”