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

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 (TDP-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. Amiotrofična lateralna skleroza (ALS) i frontotemporalna demencija (FTD) neurodegenerativni su poremećaji koji su povezani znakovima pogoršanja motoričkih i kognitivnih funkcija i kratkim vremenom preživljavanja. Uzrok je nepoznat i trenutačno ne postoji učinkovita terapija, tek lijek Riluzol i obećavajuća nova tvar arimoclomol za liječenje ALS-a. Preklapanje između ALS-a i FTD-a odvija se na kliničkoj, genetičkoj i patološkoj razini. Većina slučajeva ALS-a je sporadična (SALS), a podskupina bolesnika ima naslijeđeni oblik bolesti, obiteljski ALS (FALS), sa zajedničkom mutacijom SOD1, koja je prisutna i kod SALS-a. Nekoliko mutiranih gena koji su utvrđeni u FALS-u, pronađeni su i u SALS-u. Nedavno je utvrđeno da ponavljajući sljedovi heksanukleotida u genu C9orf72 sadrže najveću frakciju mutacija koje uzrokuju ALS i FTD, koja je poznata do danas. TAR DNA-povezujući protein 43 (TDP-43), koji kodira gen TARDBP, identificiran je kao patološki protein FALS-a, SALS-a i rjeđe FTD-a. Rjeđa TDP-43 patologija u drugim oblicima obiteljskoga FTD-a vezana je uz niz mutacija u GRN-u, FUS/TLS-u, rijetko VCP-u i drugim genima. TDP-43 i FUS/ TLS imaju velike strukturne i funkcionalne sličnosti, koje najvjerojatnije impliciraju izmijenjeno procesiranje RNA kao glavni događaj u patogenezi ALS-a. Kliničko preklapanje simptoma FTD-a i ALS-a nadopunjuje se preklapajućom neuropatologijom, s unutarstaničnim inkluzijama koje se sastoje od proteina tau povezanog s mikrotubulima, TDP-43 i rjeđe FUS-a ili nepoznatih ubikvitiniranih proteina. Nadalje, pojavljuju se novi terapijski pristupi koji ciljaju na SOD1, TDP-43 ili GRN proteine. Ovaj pregledni rad daje uvid u nova saznanja o molekularnim mehanizmima obiju bolesti koja bi se potencijalno mogla pretvoriti u nove mogućnosti liječenja.