Molecular basis of ALS and FTD: implications for translational studies / Molekularna osnova ALS-a i FTD-a: implikacije za translacijska istraživanja

Abstract

Amyotrophic lateral sclerosis (ALS) and frontotemporal dementia (FTD) are neurodegenerative disorders, related by signs of deteriorating motor and cognitive functions, and short survival. The cause is unknown and no effective treatment currently exists. For ALS, there is only a drug Riluzole and a promising substance arimoclomol. The overlap between ALS and FTD occurs at clinical, genetic, and pathological levels. The majority of ALS cases are sporadic (SALS) and a subset of patients has an inherited form of the disease, familial ALS (FALS), with a common SOD1 mutation, also present in SALS. A few of the mutant genes identified in FALS have also been found in SALS. Recently, hexanucleotide repeat expansions in C9ORF72 gene were found to comprise the largest fraction of ALS-and FTD-causing mutations known to date. TAR DNA-binding protein 43 , encoded by the TARDBP gene, has been identified as the pathological protein of FALS, SALS and, less frequently, FTD. The less frequent TDP-43 pathology in other forms of familial FTD has been linked to a range of mutations in GRN, FUS/TLS, rarely VCP, and other genes. TDP-43 and FUS/TLS have striking structural and functional similarities, most likely implicating altered RNA processing as a major event in ALS pathogenesis. The clinical overlap of the symptoms of FTD and ALS is complemented by overlapping neuropathology, with intracellular inclusions composed of microtubule-associated protein tau, TDP-43 and less frequently FUS, or unknown ubiquitinated proteins. Furthermore, new therapeutic approaches continue to emerge, by targeting SOD1, TDP-43 or GRN proteins. This review addresses new advances that are being made in our understanding of the molecular mechanisms of both diseases, which may eventually translate into new treatment options. KEY WORDS: dementia; FTLD; FUS/TLS; genetics; motor neuron disease; TDP-43; C9ORF72 nucleotide repeat expansions; TARDBP Liščić RM, Molecular basis of ALS and FTD: Implications for translational studies Arh Hig Rada Toksikol 2015;66:285-290 Amyotrophic lateral sclerosis (ALS) and frontotemporal dementia (FTD) are related neurodegenerative disorders, which are characterised by decline in motor and cognitive functions, and short survival. ALS is clinically characterised by signs of upper and lower motor neuron degeneration and its progressive spread of signs within a region or to other regions in a time frame, as defined by the revised El Escorial criteria (1). Both diseases have fatal outcome within a few years' time (1). The cause is unknown and no effective treatment currently exists. There is a drug Riluzole, which slightly prolongs survival in patients with ALS (2), and a Phase II/III randomised, placebo-controlled trials of arimoclomol (BRX-345) in familial ALS with SOD-1 mutation (NCT00706147; www.clinicaltrials.gov). The substance arimoclomol may reduce the levels of protein aggregates in motor nerves, a possible cause of ALS, by boosting expression of chaperons Hsp 70 and Hsp 90 which help newly synthesised proteins properly fol...

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