There is a clinical and pathological overlap between amyotrophic lateral sclerosis (ALS) and frontotemporal lobar degeneration (FTLD). A number of autosomal-dominant genes have been described that primarily cause ALS or FTLD such as progranulin (GRN), valosin-containing protein (VCP), and TAR DNA-Binding Protein (TARDBP), and for each of these conditions there are a small number of cases with both ALS and FTLD. Two major genes were described in 2011, which cause FTLD and/or ALS within extended kindreds. Ubiquilin2 (UBQLN2) is responsible for X-linked FTLD/ALS. A hexanucleotide repeat expansion in C9ORF72 causes chromosome 9p linked FTLD/ALS and is the most common cause of familial ALS accounting for about 40 % of familial cases. Both UBQLN2 and C9ORF72 mutations lead to TDP-43 positive neuropathology, and C9ORF72-positive cases have p62/ubiquitin-positive pathology, which is not stained by TDP-43 antibodies. Ubiquilin2 is one of a family of proteins thought to be important in targeting abnormal proteins for degradation via lysosomal and proteasomal routes. The pathogenic mechanism of the C9ORF72 expansion is unknown but may involve partial haploinsufficiency of C9ORF72 and/or the formations of toxic RNA inclusions. The identification of mutations in these genes represents an important step forward in our understanding of the clinical, pathological, and genetic spectrum of ALS/FTLD diseases.
"FTD is a group of non-Alzheimer dementias characterized by atrophy of the frontal and/or temporal lobes causing mid-life behavioral changes or language impairment (Warren et al., 2013). Over the past few years, the identification of TDP-43, C9ORF72 and UBQLN2 as genes causing ALS and FTD has suggested a similarity for both diseases (Morris et al., 2012). Similar pathogenic mechanisms have been suggested for ALS and FTD (Van Langenhove et al., 2012; Ling et al., 2013) but so far it is unclear how patients with the same genetic mutations can have either ALS, FTD or both. "
[Show abstract][Hide abstract] ABSTRACT: Neurodegenerative diseases share pathogenic mechanisms at the cellular level including protein misfolding, excitotoxicity and altered RNA homeostasis among others. Recent advances have shown that the genetic causes underlying these pathologies overlap, hinting at the existence of a genetic network for neurodegeneration. This is perhaps best illustrated by the recent discoveries of causative mutations for amyotrophic lateral sclerosis (ALS) and frontotemporal degeneration (FTD). Once thought to be distinct entities, it is now recognized that these diseases exist along a genetic spectrum. With this wealth of discoveries comes the need to develop new genetic models of ALS and FTD to investigate not only pathogenic mechanisms linked to causative mutations, but to uncover potential genetic interactions that may point to new therapeutic targets. Given the conservation of many disease genes across evolution, Caenorhabditis elegans is an ideal system to investigate genetic interactions amongst these genes. Here we review the use of C. elegans to model ALS and investigate a putative genetic network for ALS/FTD that may extend to other neurological disorders.
Frontiers in Genetics 04/2014; 5:85. DOI:10.3389/fgene.2014.00085
"The clinical phenotype for repeat expansion carriers includes older age of onset, shorter disease duration, psychotic symptoms, bulbar onset of ALS, and a predominantly behavioural variant of FTD [21–25]. The pathology of C9orf72-related disease includes TDP-43 positive inclusions and also some inclusions that are TDP-43 negative but p62/ubiquitin positive in specific parts of the brain, such as cerebellum and hippocampus [22, 25–28]. TDP-43 is a protein that is able to bind RNA, DNA, and other proteins and is mainly involved in transcription and splicing regulation . "
[Show abstract][Hide abstract] ABSTRACT: Amyotrophic lateral sclerosis (ALS) is a progressive and lethal disease of motor neuron degeneration, leading to paralysis of voluntary muscles and death by respiratory failure within five years of onset. Frontotemporal dementia (FTD) is characterised by degeneration of frontal and temporal lobes, leading to changes in personality, behaviour, and language, culminating in death within 5-10 years. Both of these diseases form a clinical, pathological, and genetic continuum of diseases, and this link has become clearer recently with the discovery of a hexanucleotide repeat expansion in the C9orf72 gene that causes the FTD/ALS spectrum, that is, c9FTD/ALS. Two basic mechanisms have been proposed as being potentially responsible for c9FTD/ALS: loss-of-function of the protein encoded by this gene (associated with aberrant DNA methylation) and gain of function through the formation of RNA foci or protein aggregates. These diseases currently lack any cure or effective treatment. Antisense oligonucleotides (ASOs) are modified nucleic acids that are able to silence targeted mRNAs or perform splice modulation, and the fact that they have proved efficient in repeat expansion diseases including myotonic dystrophy type 1 makes them ideal candidates for c9FTD/ALS therapy. Here, we discuss potential mechanisms and challenges for developing oligonucleotide-based therapy for c9FTD/ALS.
Journal of nucleic acids 11/2013; 2013:208245. DOI:10.1155/2013/208245
"The discovery was important because the gene appears to be the most common cause of ALS. In addition to its prominent role in ALS in many populations, C9ORF72 is important because REs in the gene are also a cause of frontotemporal dementia (FTD) which has long been considered to be related to ALS (Boeve et al., 2012; Ferrari et al., 2012; Lillo and Hodges, 2009; Morris et al., 2012; Neumann et al., 2006; Simón-Sánchez et al., 2012). The expansions have even been reported in a few patients diagnosed with Alzheimer's disease , corticobasal syndrome, supranuclear palsy, and olivopontocerebellar degeneration, emphasizing the relation between various neurologic disorders (Lesage et al., 2013; Lindquist et al., 2013; Wojtas et al., 2012). "
[Show abstract][Hide abstract] ABSTRACT: Amyotrophic lateral sclerosis (ALS) is the most common motor neuron disease in populations of European descent. It was recently found that a hexanucleotide repeat expansion in C9ORF72 is its most common cause in these populations. The contribution of C9ORF72 to ALS is notably lower in the Far East, but its role in other populations is unknown. Results of C9ORF72 screening in 78 unrelated Iranian ALS patients are reported here. The repeat expansion was observed in only 1 (5.9%) of the familial and 1 (1.6%) of the sporadic cases. These figures are to be compared, respectively, with 30% and 6.9% among patients of European ethnicity. Screenings of C9ORF72 in other Middle East countries will reveal whether the low contribution of C9ORF72 to ALS is a feature of the entire region. During the screenings, it was noted that in a single family, 3 individuals affected with ALS, Parkinson's disease, or frontotemporal dementia all carried the repeat expansion. The finding suggests the mutation does rarely contribute to the etiology of Parkinson's disease.
Neurobiology of aging 08/2013; 35(1). DOI:10.1016/j.neurobiolaging.2013.07.016 · 5.01 Impact Factor
Yazi D Ke, Annika van Hummel, Claire H Stevens, Amadeus Gladbach, Stefania Ippati, Mian Bi, Wei S Lee, Sarah Krüger, Julia van der Hoven, Alexander Volkerling, Andre Bongers, Glenda Halliday, Nikolas K Haass, Matthew Kiernan, Fabien Delerue, Lars M Ittner
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