ReviewDissection of genetic factors associated with amyotrophic lateral sclerosis
Introduction
The term “amyotrophic lateral sclerosis” was coined by the French neurologist Jean-Martin Charcot in the 1800s when he wrote a detailed clinical and pathological description of this disease. “Amyotrophic” means muscular atrophy, and, “lateral sclerosis” describes the scarring or hardening tissues in the lateral spinal cord. More precisely, the major neuropathological features of ALS are: (1) degeneration of the corticospinal tract, which contains axons projecting from the primary motor cortex to the motor neurons, and extensive loss of lower motor neurons from the anterior horns of the spinal cord (SC) and brainstem (Ghatak et al., 1986, Hughes, 1982); (2) degeneration and loss of Betz cells (large pyramidal cell neurons) in the primary motor cortex, which project their axons to the lower motor neurons via the corticospinal tract (Hammer et al., 1979, Maekawa et al., 2004, Udaka et al., 1986); (3) and reactive gliosis, which corresponds to hypertrophy of glial cells (with either a loss of their neuroprotective ability or a gain of neurotoxic effects) in the motor cortex and SC around the areas of degeneration (Ekblom et al., 1994, Kawamata et al., 1992, Murayama et al., 1991, Schiffer et al., 1996). ALS typically starts focally, in a particular segment of the body; either an upper limb or a lower limb (spinal form) or the bulbar region. After the focal initiation, which is usually asymmetric, symptoms spread to other regions over time and some evidence suggests that the spread may be mediated by non-cell autonomous propagation or “prion-like propagation” (Kanouchi et al., 2012). A common feature of many neurodegenerative diseases, including ALS, is the formation of protein aggregates/inclusions in degenerating motor neurons. It is noteworthy that, even though these pathological structures were first observed several decades ago, their presence still remains a topic of considerable debate and they have been independently proposed to be toxic, harmless, or even protective. The exact composition of these protein structures remains largely unknown but the seminal observation of cytoplasmic inclusions containing TDP-43 (TAR-DNA binding protein 43) (Arai et al., 2006, Neumann et al., 2006) or FUS (fused in sarcoma) (Ling et al., 2010) has now become hallmark pathological feature of the disease (TDP-43+ for most cases and FUS+ for a small subset of cases). So far, most studies have shown TDP-43 and FUS pathologies to be mutually exclusive, thereby implying independent pathways (Neumann et al., 2009, Seelaar et al., 2010, Vance et al., 2009). Nonetheless, the possibility of interactions between TDP-43 and FUS, as well as their association with other ALS associated proteins, is now an open field of investigation (Mackenzie et al., 2010). Interestingly, the neuronal distribution and prion-like propagation of phosphorylated TDP-43 inclusions now enable pathologists to distinguish four neuropathological stages for ALS (Brettschneider et al., 2013). Up to 50% of ALS patients may also have symptoms and signs of frontotemporal dementia (FTD) with degeneration in the frontotemporal regions of the brain (Liscic et al., 2008). ALS is almost always a fatal disease with progressive muscular weakness and atrophy followed by progressive muscular paralysis, which commonly leads to death through respiratory failure. While significant advances have been made in palliative therapies, there is no cure or means to significantly slow disease progression. Indeed, currently only one CADTH/FDA-approved therapy exists (Riluzole) which only offers a modest slowing of disease progression. The aim of this review is to outline the genetic methodologies used to identify loci and genes associated with ALS, and to decipher the genetic factors involved in this disease.
Section snippets
Epidemiology of ALS
ALS is a rare disease with a mean incidence of 2.8/100,000 in Europe and 1.8/100,000 in North America, and a mean prevalence of 5.40/100,000 in Europe and 3.40/100,000 in North America (Chio et al., 2013a). Men are slightly more frequently affected than women with a male:female incidence rate ratio of 1.4 (Logroscino et al., 2010). The median survival period following onset is independent of gender and is usually 2–4 years (Chio et al., 2009a). In most cases, disease onset is during
Emergence of genetic susceptibility
The idea of genetic factors being involved in ALS first emerged in 1850 with the publication of several reports highlighting cases with a familial or hereditary history (Strong et al., 1991). Over the past decades it has recurrently been stated that the fraction of ALS cases with a family history, which are often referred to as FALS, is approximately 10%. However, a recent meta-analysis made to establish the rate of FALS using prospective population based registries has indicated that it is
Linkage analysis
Many ALS pedigrees show classic Mendelian patterns of inheritance suggestive of highly penetrant mutations. FALS is mainly inherited in an autosomal dominant manner but autosomal recessive and X-linked inheritance have been reported (Deng et al., 2011, Gros-Louis et al., 2006, Hadano et al., 2001). Genetic traits showing Mendelian inheritance can be studied by linkage analysis which involves the calculation of the overall likelihood that a specific condition segregating in a specific pedigree
Genetic landscape of ALS
Through a number of different genetic approaches and studies, several genes associated with ALS have been identified and over 110 are listed on ALSoD (Abel et al., 2012), a public website for ALS genetic research. Nevertheless, it remains difficult to discriminate between strong and weak associations, high and low penetrance and private (observed in a single family)/rare versus relatively common causes, since most of these genes remain only candidates owing to a requirement for replication
Oligogenic model in ALS?
Recently, several studies have reported ALS/FTD cases with mutations in more than one ALS gene in the same individual. Because the C9ORF72 repeat expansion is the most common cause of ALS, many co-occurrences have been observed to involve a C9ORF72 expansion alongside another mutation in one of the following genes: GRN (van Blitterswijk et al., 2013a), ANG (Lattante et al., 2012, Millecamps et al., 2012), DAO (Millecamps et al., 2012), MAPT (King et al., 2013, van Blitterswijk et al., 2013a),
Locus 9p21—C9ORF72
As mentioned above, the 9p21 locus was first identified using linkage analyses. This finding was replicated in several studies and the combined data defined a minimum linkage region of 3.7 Mb containing only five known genes (Boxer et al., 2011, Gijselinck et al., 2010, Hosler et al., 2000, Morita et al., 2006, Valdmanis et al., 2007, Vance et al., 2006). Several independent GWA studies confirmed the implication of this locus in the spectrum of ALS and frontotemporal dementia (FTD) by
Conclusion
The different genetic approaches discussed here underscore the fact that studying ALS pedigrees through a combination of linkage analysis and sequencing (whole exome or targeted sequencing) remains the most successful approach for finding genes associated with ALS. GWA studies have failed to identify common variants contributing to the etiology of SALS, unlike in other diseases where GWA studies have successfully identified genetic risk factors (e.g. the association of Restless Legs Syndrome
Acknowledgments
Rouleau GA has received ALS-related funding from the Canadian Institutes of Health, the Muscular Dystrophy Association ALS Division, the ALS Association and the ALS Society of Canada.
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