Recent advances in the genetics of the ALS-FTLD complex.
ABSTRACT 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.
- SourceAvailable from: Xerardo García-Mera[Show abstract] [Hide abstract]
ABSTRACT: In a multi-target complex network, the links (Lij) represent the interactions between the drug (di) and the target (tj), characterized by different experimental measures (Ki, Km, IC50, etc.) obtained in pharmacological assays under diverse boundary conditions (cj). In this work, we handle Shannon entropy measures for developing a model encompassing a multi-target network of neuroprotective/neurotoxic compounds reported in the CHEMBL database. The model predicts correctly >8300 experimental outcomes with Accuracy, Specificity, and Sensitivity above 80%-90% on training and external validation series. Indeed, the model can calculate different outcomes for >30 experimental measures in >400 different experimental protocolsin relation with >150 molecular and cellular targets on 11 different organisms (including human). Hereafter, we reported by the first time the synthesis, characterization, and experimental assays of a new series of chiral 1,2-rasagiline carbamate derivatives not reported in previous works. The experimental tests included: (1) assay in absence of neurotoxic agents; (2) in the presence of glutamate; and (3) in the presence of H2O2. Lastly, we used the new Assessing Links with Moving Averages (ALMA)-entropy model to predict possible outcomes for the new compounds in a high number of pharmacological tests not carried out experimentally.International Journal of Molecular Sciences 01/2014; 15(9):17035-17064. · 2.34 Impact Factor
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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 01/2014; 5:85.
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ABSTRACT: Amyotrophic lateral sclerosis (ALS) is a devastating neurodegenerative disease that results in progressive degeneration of motor neurons, ultimately leading to paralysis and death. Approximately 10% of ALS cases are familial, with the remaining 90% of cases being sporadic. Genetic studies in familial cases of ALS have been extremely informative in determining the causative mutations behind ALS, especially as the same mutations identified in familial ALS can also cause sporadic disease. However, the cause of ALS in approximately 30% of familial cases and in the majority of sporadic cases remains unknown. Sporadic ALS cases represent an underutilized resource for genetic information about ALS; therefore, we undertook a targeted sequencing approach of 169 known and candidate ALS disease genes in 242 sporadic ALS cases and 129 matched controls to try to identify novel variants linked to ALS. We found a significant enrichment in novel and rare variants in cases versus controls, indicating that we are likely identifying disease associated mutations. This study highlights the utility of next generation sequencing techniques combined with functional studies and rare variant analysis tools to provide insight into the genetic etiology of a heterogeneous sporadic disease.PLoS Genetics 10/2014; 10(10):e1004704. · 8.17 Impact Factor