Genetics of FTLD: overview and what else we can expect from genetic studies

Abstract

Frontotemporal lobar degeneration (FTLD) comprises a highly heterogeneous group of disorders clinically associated with behavioral and personality changes, language impairment, and deficits in executive functioning, and pathologically associated with degeneration of frontal and temporal lobes. Some patients present with motor symptoms including amyotrophic lateral sclerosis. Genetic research over the past two decades in FTLD families led to the identification of three common FTLD genes (microtubule-associated protein tau, progranulin, and chromosome 9 open reading frame 72) and a small number of rare FTLD genes, explaining the disease in almost all autosomal dominant FTLD families but only a minority of apparently sporadic patients or patients in whom the family history is less clear. Identification of additional FTLD (risk) genes is therefore highly anticipated, especially with the emerging use of next-generation sequencing. (FUS, EWS, TAF15); MAPT, microtubule-associated tau gene; CBD, corticobasal degeneration; PSP, progressive supranuclear palsy; GGT, globular glial tauopathies; AGD, argyrophilic grain disease; AD, Alzheimer's disease; TDP-43, TAR DNA-binding protein; FUS, fused in sarcoma; aFTLD-U, atypical-FTLD-U; EWS, ewing in sarcoma; TAF15, TATA-binding protein-associated factor 15; FTDP-17, frontotemporal dementia and parkinsonism linked to chromosome 17; cM, centimorgan; PiD, Pick's disease; MT, microtubule; NFTs, neurofibrillary tangles; iPSC, induced pluripotent stem cells; GRN, progranulin; CSF, cerebrospinal fluid; CBS, corticobasal syndrome; NCL, neuronal ceroid lipofuscinosis; SAHA, suberoylanilide hydroxamic acid; C9orf72, chromosome 9 open reading frame 72; DPRs, dipeptide repeat proteins; DENN, differentially expressed in normal and neoplasia; GEF, guanine nucleotide exchange factors; CHMP2B, charged multivesicular body protein 2B; ESCRT-III, endosome sorting complex required for transport 3; VCP, valosin-containing protein gene; IBM, inclusion body myopathy; PDB, paget disease of the bone; IBMPFD, inclusion body myopathy with Paget disease of the bone and frontotemporal dementia; MSP, multisystem proteinopathy; hnRNPA1, heterogeneous nuclear ribonucleoprotein A1; hnRNPA2B1, heterogeneous nuclear ribonucleoprotein A2/B1; SQSTM1, sequestosome 1; TBK1, TANK binding kinase 1; OPTN, optineurin; TRN1, transportin; CHCHD10, coiled-coil-helix-coiled-coil-helix domain containing 10; MICOS, mitochondrial contact site and cristae organization system; UBQLN2, ubiquilin 2; DCTN1, dynactin 1; CSF1R, colony stimulating receptor factor 1 gene; PRKAR1B, protein kinase A type I-beta regulatory subunit gene; TREM2, triggering receptor expressed on myeloid cells 2 gene; TMEM106B, the transmembrane protein 106B gene; GWAS, genome-wide association study; SNP, single nucleotide polymorphism; CTSC, cathepsin C; ATXN2, ataxin 2 gene; APOE, apolipoprotein E; PRNP, prion protein and UNC13A unc-13 homolog A, C. elegans; ANG, angiogenin; GENFI, genetic and frontotemporal dementia initiative; LEFFTDS, Longitudi...

The Lysosomal Trafficking Transmembrane Protein 106B Is Linked to Cell Death

“…Clinical characteristics include changes in personality and behavior and difficulties with language. Approximately 25-50% of FTLD cases are genetically inherited, and several genes, such as GRN (the gene encoding progranulin), MAPT, VCP, CHAMP2B, TARDBP, FUS, and C9ORF72, have been identified as FTLD-causative genes (3). FTLD has been recently recognized as a disease that has a common pathogenetic background with amyotrophic lateral sclerosis (ALS) (4).…”

“…7D). Finally, multiple genes related to the lysosomal and ubiquitin-proteasome degradation pathway, such as CHAMP2B, SQSTM1, VCP, and UBQLN2, have been identified as familial FTLD-causative genes (3). These data suggest that the dysfunction of the lysosome and/or ubiquitin-proteasome degradation pathways, as observed in FTLD-TDP patients (23,39), may increase the steady-state levels of TMEM106B-FL and TMEM106B-NTFs, which probably contributes to the pathogenesis of some FTLD cases.…”

Paving the road for the study of epigenetics in neurodegenerative diseases

“…The most common cause of FTLD and ALS is a hexanucleotide repeat in the first intron of the C9ORF72 gene [3,14]. Because the mutation is located on a non-coding region, it has been postulated that this mutation and any other change that affect C9ORF72 gene expression could be also involved in disease [13]. As a result, multiple groups have interrogated the role of methylation in C9ORF72 in expansion repeat carries and not carriers, as explained by Belzil et al, in their review of FTLD and ALS epigenetics included in this cluster [1].…”

Predementia Brain Changes in Progranulin Mutation: A Systematic Review of Neuroimaging Evidence

“…In 2006, mutations in the gene encoding progranulin ( GRN ) on chromosome 17q21 have emerged as a major cause of such familial forms[2]. To date, over 70 pathogenic GRN mutations have been identified, all uniformly leading to a loss of about 50% in progranulin levels through haploinsufficiency and to intraneuronal aggregation of TDP-43 protein[3]. Despite this common mechanism, FTD due to GRN mutations (FTD- GRN ) is clinically variable even among individuals carrying the same mutation[3].…”

“…To date, over 70 pathogenic GRN mutations have been identified, all uniformly leading to a loss of about 50% in progranulin levels through haploinsufficiency and to intraneuronal aggregation of TDP-43 protein[3]. Despite this common mechanism, FTD due to GRN mutations (FTD- GRN ) is clinically variable even among individuals carrying the same mutation[3]. Behavioral variant FTD (bvFTD) is by far the most common presentation, followed by non-fluent variant of primary progressive aphasia [4].…”