Abstract
Frontotemporal dementia (FTD) is a progressive brain disease characterized by atrophy of the frontal and anterior temporal lobes. The prevalence has been estimated between 10 and 30 per 100,000, and patients have severe changes in personality and behavior. The disease has a strong genetic component, and in up to 40 % of cases, a positive family history has been observed. To date, seven disease genes have been identified, of which MAPT, GRN, and C9orf72 are most frequently mutated. In contrast to familial FTD, far less is known about sporadic FTD. GWAS reported TMEM106B as an important risk factor for FTD, and recently, new loci have been associated with the disease. In this chapter, we summarize the current insights into the genetics of FTD based on neuropathological and functional data.
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Introduction
Frontotemporal dementia (FTD) is a devastating presenile dementia characterized by atrophy of the frontal and anterior temporal lobes, and the prevalence, in the age group between 45 and 65 years, has been estimated between 10 and 30 per 100,000 [1]. It is a heterogeneous group of disorders and associated with genes that typically cause a clinical picture of amyotrophic lateral sclerosis (ALS), the most common type of motor neuron disease (MND) [2].
Clinically, there is progressive deterioration of either behavior or language, which translates into two FTD subtypes: the behavioral variant of frontotemporal dementia (bvFTD) and primary progressive aphasia (PPA). In bvFTD, patients have severe changes in behavior and personality, as indicated by early disinhibition, apathy, loss of sympathy, perseverative and stereotypic behavior, and hyperorality [3]. PPA can be further subdivided into semantic variant PPA (svPPA) and nonfluent variant PPA (nfvPPA), based on specific speech and language features. A third recognized subtype for patients not fitting either category is logopenic variant primary progressive aphasia (lvPPA) [4, 5]. The bvFTD accounts for more than 50 % of the FTD patients, and PNFA is the second most prevalent presentation of FTD, accounting for 25 %. The svPPA presents in 20–25 % of the FTD patients, and lvPPA is not considered part of the FTD group of disorders [6, 7]. Other conditions closely related to FTD are MND, progressive supranuclear palsy (PSP) syndromes, corticobasal syndrome (CBS), FTD with parkinsonism (FTDP), and argyrophilic grain disease (AGD) [8].
At the neuropathological level, the different subtypes of FTD present with diverse patterns of frontal and anterior temporal lobe atrophy. The term “frontotemporal lobar degeneration” (FTLD) is often used for these pathological conditions that present with FTD. FTLD is a proteinopathy characterized by abnormal, ubiquitinated protein inclusions in the cytoplasm or nuclei of neuronal and glial cells. Neuronal loss and astrocytosis are seen in cortices of atrophied frontal and temporal lobes, and neuropathological subcategories are based on the major constituent of inclusions [9]. Initially, two pathological categories were described: FTLD-tau including Pick’s disease, in which neurons and glial cells contained inclusions of hyperphosphorylated tau protein, and FTLD-Ubiquitin or FTLD-U with unknown inclusions. In 80–95 % of the FTLD-U group, inclusions were later found to be mainly composed of TDP-43 (FTLD-TDP), and a considerable number of TDP-43-negative FTLD-U cases had inclusion of FUS (FTLD-FUS) [10, 11]. In a small number of FTLD-U patients, the inclusion protein remains unknown (FTLD-UPS) [12].
In up to 40 % of FTD cases, a positive family history is observed and inheritance varies among the different clinical subtypes [13–15]. Family history is most prominent in bvFTD, especially when MND is present. Research on these families has led to the discovery of multiple disease-causing genes. Mutations in microtubule-associated protein tau (MAPT) [16–18], granulin (GRN) [19, 20], and chromosome 9 open reading frame 72 (C9orf72) [21, 22] together explain the majority of familial FTD cases [1, 23]. Mutations in valosin-containing protein (VCP) and charged multivesicular body protein 2B (CHMP2B) are rare, each explaining less than 1 % of the familial FTD [1]. Mutations in common ALS genes TAR DNA-binding protein (TARDBP) and fused in sarcoma (FUS) are a very rare cause of familial FTD [24–27]. Association between affected gene and associated neuropathology is observed, and the association between disease gene and clinical phenotype is limited (Table 5.1) [1]. In contrast to familial forms of FTD, far less is known about the genetics of sporadic forms of the disease. To date, two genome-wide association studies (GWAS) have been published in which TMEM106B at chromosome 7p21 has been reported as a risk factor for FTLD-TDP [28] and novel genetic risk loci and pathways have been associated with FTD [29].
MAPT
In the late 1990s, linkage at chromosome 17q21 was found for multiple families in FTD and parkinsonism linked to chromosome 17 (FTDP-17). Three research groups found mutations in and around MAPT exon 10 and proved that dysfunction of the protein tau is sufficient to cause neurodegeneration and dementia [16–18]. Accumulation of tau occurs primarily as insoluble fibrils in neuronal cell bodies (neurofibrillary tangles (NFTs)) and processes (neuropil threads or dystrophic neurites), but can also accumulate in astrocytes and microglia. Tau deposits are characteristic for a large number of neurodegenerative diseases known as the “tauopathies,” which include Alzheimer’s disease (AD), Pick’s disease (PiD), PSP, corticobasal degeneration (CBD), and AGD [30]. In AD, all six brain isoforms of tau are found in inclusions [31], and in FTDP-17, inclusions are heterogeneous, with different mutations associated with a different isoform composition. For PSP, CBD, and AGD, inclusions consist mainly of 4-repeat tau [32–34], and PiD has predominantly 3-repeat tau deposits [35]. In populations of European descent, MAPT is characterized by two haplotypes, H1 and H2, which result from a 900-kb inversion polymorphism. Inheritance of the H1 haplotype is a risk factor for PSP, CBD, and idiopathic Parkinson’s disease. The H2 haplotype is associated with increased expression of exon 3, suggesting that inclusion of this exon might be protective [36–39].
Tau proteins are microtubule-associated proteins that are abundant in the central nervous system (CNS) and mainly concentrated in axons [40]. The MAPT gene is located on chromosome 17q21 and consists of 16 exons, as depicted in Fig. 5.1. In adult human brain, alternative mRNA splicing of exons 2, 3, and 10 produces six tau isoforms ranging from 352 to 441 amino acids. Three of these isoforms contain 4 microtubule-binding repeats (4R), whereas the other three contain only 3 microtubule-binding repeats (3R). The extra repeat domain is encoded by exon 10. The presence or absence of a 29 amino acid (exon 2) or a 58 amino acid (exons 2 and 3) insert in the N-terminal half of the protein divides the isoforms further in 0N, 1N, and 2N (Fig. 5.1). The ratio of 4R and 3R tau isoforms in the cerebral cortex of healthy adults is equal, while in fetal brain, only 3R0N is expressed. Most adult rodents express isoforms with four repeats [41]. Tau is enriched in neurons and has an important function in promoting microtubule assembly and stability [42–44]. The C-terminal repeat domains bind microtubules directly, and 4R tau promotes microtubule assembly 3-fold stronger than 3R tau [45, 46]. The N-terminal inserts are part of the projection domain, establishing the interaction of tau and microtubules with the plasma membrane [47, 48]. In addition to its role in microtubule assembly, tau mediates transport of vesicles and organelles along the microtubules by regulating attachment and detachment of motor proteins [49, 50]. The motility of motor proteins dynein and kinesin is differentially regulated and dependent on tau concentration and isoform, pointing to a balanced spatiotemporal regulation of axonal transport [51]. Literature also suggests a physiological role for tau in dendrites, which might be an important function mediating synaptic impairment early in the disease process [52, 53].
Phosphorylation is the major posttranslational modification of tau protein, and in diseased brain, tau is abnormally hyperphosphorylated, generating paired helical filaments (PHFs) and neurofibrillary tangles [54–56]. The degree of tau phosphorylation influences its interaction with microtubules. Abnormal hyperphosphorylated tau sequesters normal tau, leading to misfolding, co-aggregation, and inhibition of microtubule assembly [57]. Microtubule-associated proteins 1 and 2 are also sequestered from pre-assembled microtubules, leading to their disruption [58–61]. There are 80 serine/threonine and 5 tyrosine potential phosphorylation sites, and normal brain tau contains 2–3 mol of phosphate per mole of tau protein. Mass spectrometry and antibody staining have identified more than 40 serine/threonine hyperphosphorylation sites of tau in AD [62, 63]. The phosphorylation of tau itself is developmentally regulated, and fetal tau is more phosphorylated than adult brain tau [64]. Several protein kinases are known to phosphorylate tau, and hyperphosphorylation probably involves coordinated action of several of them [65, 66]. When tau hyperphosphorylation induces dissociation from microtubules, it is redistributed from axonal to somatodendritic compartments. The increased pool of hyperphosphorylated tau is thought to promote assembly into fibrillar aggregates. In addition to phosphorylation, tau undergoes other posttranslation modifications, such as acetylation, glycation, glycosylation with O-linked N-acetylglucosamine, nitration, ubiquitination, sumoylation, prolyl isomerization, and truncation, all of which affect tau phosphorylation and/or aggregation [30].
Pathological MAPT Mutations
Up to 44 different clinical MAPT mutations in 134 FTD families have been reported in exons 1, 9, 10, 11, 12, and 13, intron 9, and the first 19 nucleotides of intron 10 (detailed information on each MAPT mutation is available at www.molgen.ua.ac.be/ftdmutations) [67, 68]. Except for mutations P301L in exon 10 and E10 + 16 in intron 10, identified in 32 families and 27 families, respectively, MAPT mutations are rare and seen in single families. Mutations are mainly clustered in exons 9–12, encoding the four microtubule-binding domains of tau, and can be divided into two functional groups. The first group has a primary effect at the protein level and includes missense and deletion mutations in the coding region of the gene. These mutations reduce the ability of tau to interact with microtubules, and some mutations promote filament assembly [68, 69]. The second group affects alternative splicing of tau pre-mRNA. This includes intronic and exonic mutations that alter alternative mRNA splicing of MAPT exon 10. The intronic mutations are clustered at the exon 10/intron 10 junction that is predicted to form a stem-loop structure protecting the 5′-splice site [70, 71]. Most of these mutations increase exon 10 inclusion and raise the normal 4R/3R isoform ratio from 1 to 2–3 [16]. However, a few mutations such as Δ(delta)K280 enhance exon 10 exclusion and result in increased expression of 3R tau [72]. In FTDP-17, the early clinical symptoms vary with the type of mutation found, and there is considerable phenotypic variability [73].
Tau Animal Models
After the identification of pathogenic mutations in MAPT in FTDP-17, several groups reported on the formation of NFTs and neuronal death in mouse models expressing human mutant tau, reviewed by Götz et al. [74]. To study the link between NFTs and brain dysfunction, transgenic mice were created expressing human P301L mutant tau that could be suppressed by doxycycline. This model (rTg4510) develops progressive age-related NFTs, neuronal loss, and behavioral impairment [75]. After switching off transgenic tau expression, memory function recovers and the number of neurons stabilizes, while NFTs continue to accumulate. Additional studies in rTg4510 showed that neuron loss can occur independently of NFT pathology and not all regions with NFT pathology undergo neuron loss, together implying that NFTs alone are not sufficient to cause cognitive decline or neuronal death [76, 77]. In vivo imaging shows that tangle-bearing neurons are long-lived and soluble tau species may be the critical components underlying neurodegeneration [78]. In transgenic mice expressing mutant repeat domains of human tau, similar observations were made [79]. After turning off expression of pro-aggregant Δ(delta)K280 mutant repeat domains of tau, memory and long-term potentiation recovers, while neuronal loss and aggregates persist. When anti-aggregant mutations were added, neuronal death was prevented, but tau aggregates are still formed [80].
There is accumulating evidence for intercellular transfer of tau aggregates [81–83]. In one of the first studies, brain homogenates from mice expressing human mutant P301S tau protein (with silver-positive tau inclusions) were injected into mice expressing human wild-type tau. This induced filament formation of wild-type human tau and spreading of pathology over time to anatomically connected brain regions [81]. Additional work showed that synthetic tau fibrils assembled from human mutant tau protein promoted the formation of tau inclusions in presymptomatic mice transgenic for human mutant P301S tau protein. In these mice, spreading of tau pathology was also initiated [84]. This has been further supported by experiments in a mouse model expressing human tau P301L restricted to layer II of the entorhinal cortex, recreating an early stage of NFT pathology [85]. Recently, similar results were obtained after injection of brain homogenates from cases of human tauopathies (including AD, PiD, AGD, PSP, and CBD) [86]. One other study demonstrated the induction and propagation of pathology when tau oligomers from AD brain were injected into wild-type mice, suggesting that they might play a critical role in initiation and spreading of tau pathology [87]. In vitro studies also showed induction and propagation of tau misfolding, and involvement of the endocytic pathway has been suggested [83, 88–91]. These studies show that tau fibrils spread from cell to cell by converting soluble tau into aggregates, and this mechanism might be responsible for disease propagation.
Besides the mouse, other organisms have been used to study FTD, such as the fruit fly Drosophila melanogaster, the nematode Caenorhabditis elegans, and the zebrafish Danio rerio. When wild-type and FTDP-17 mutant forms of human tau (R406W) were expressed in Drosophila, flies exhibited adult-onset progressive neurodegeneration, early death, enhanced toxicity of mutant tau, and abnormal tau accumulation without NFT formation [92]. Expression of wild-type and mutant human tau (P301L and V337M) in the C. elegans led to progressive uncoordinated locomotion, accumulation of insoluble tau species, neurodegeneration, and loss of neurons [93]. Expression of mutant tau caused an earlier and more severe phenotype compared to wild-type tau. Stable expression of human tau with the P301L mutation in the zebrafish also recapitulates key pathological features of tauopathies, including tau hyperphosphorylation, tangle formation, behavioral disturbances, and neuronal cell death [94].
GRN
In a large number of families linked to chromosome 17q21, mutations in MAPT could not be identified. In 2006, systematic analyses of the 17q21 region led to the discovery of mutations in GRN as a cause of FTLD-U [19, 20]. All GRN-associated FTLD patients present with TDP-43-positive inclusions in the affected cortical regions and basal ganglia (FTLD-TDP), often accompanied by irregular and short dystrophic neurites [95, 96]. The inclusions are found in neurons and glial cells and can be cytoplasmic as well as intranuclear. NFTs, neuritic plaques, and Lewy bodies have occasionally been observed in GRN brains [97–100].
In humans, the GRN gene is located upstream to the MAPT gene and comprises 12 coding exons (Fig. 5.2) [101]. The gene encodes progranulin, a 593-amino-acid-long protein containing a secretory signal sequence and seven and a half repeats of a unique 10–12 cysteine-containing motif. This motif is highly conserved in evolution and a reminiscent of the epithelial growth factor [102–105]. Progranulin is expressed in several tissues of the periphery as well as in neurons and microglia in the central nervous system, and little or no expression has been detected in adult astrocytes and oligodendrocytes [102, 106–108]. A GWAS implicated sortilin (SORT1) as an important regulator of GRN levels in human plasma, and cellular studies showed that SORT1 is a major neuronal receptor for GRN [109, 110]. SORT1 facilitates extracellular GRN clearance via endocytosis and delivery to the lysosomes. When GRN interaction with SORT1 is impaired, it is possible to restore extracellular GRN levels in FTD patient-derived lymphocytes and induced pluripotent stem cells (iPSC) differentiated to neurons [111].
GRN plays a key role in several biological processes including cell growth, wound repair, inflammation, and neuron development [112]. Studies in different cellular models show that GRN expression enhances neuronal survival and promotes neurite outgrowth and branching, while siRNA-mediated GRN knockdown results in reduced neurite arborization and dendritic protrusions [113–117]. The exact mechanism through which GRN exerts its neurotrophic function is not completely understood; however, compelling evidence suggests the involvement of the phosphatidylinositol 3-kinase/Akt signaling pathway and glycogen synthase kinase-3 beta regulation [118–120]. GRN-deficient cells show increased caspase activation, decrease in cellular survival, and vulnerability to a number of cellular stressors, including oxygen and glucose deprivation, oxidative stress, and sublethal doses of N-methyl-D-aspartic acid, kinase inhibitors, and proteasomal inhibitors [118, 121–123].
It has been hypothesized that GRN performs a neuroprotective role in the CNS by stimulating production of anti-inflammatory Th2 cytokines and supporting neuroprotective inflammation by binding to TNF receptors [124, 125]. The anti-inflammatory effects of GRN are evident in Grn−/− mice that show an exacerbated inflammatory reaction [123]. Moreover, increased GRN expression has been observed in microglia following a variety of acute and chronic insults in several neurodegenerative disorders including Creutzfeldt-Jakob disease [126], ALS [127, 128] and FTLD [99]. It also attracts and activates microglia, enhancing endocytosis of extracellular peptides such as amyloid β (beta) 1–42 [129]. Interestingly, microglia of patients with GRN mutations are able to upregulate GRN despite reduced levels in blood, cerebrospinal fluid, and neurons in unaffected brain regions [99] suggesting GRN plays a central role in the inflammatory response.
Pathological GRN Mutations
Confirmed pathogenic mutations in GRN cases have been so far identified only in FTLD-TDP, and GRN mutation screening in patients with ALS [130, 131], Parkinson’s disease [132], and non-FTD cases with TDP-43 pathology [133] yields no positive results. To date, 69 pathogenic mutations have been observed in patients with FTLD-TDP, mostly being loss-of-function mutations suggesting that GRN haploinsufficiency is the major pathogenic mechanism (detailed information on each GRN mutation is available at www.molgen.ua.ac.be/ftdmutations) [67]. GRN deficiency occurs through frame-shift, splice site, and nonsense mutations, introducing a premature termination codon with activation of nonsense-mediated mRNA decay and reduction of progranulin protein levels [19, 20, 134]. Loss of mRNA translation and consequent protein haploinsufficiency is also observed when mutations are present in the Kozak sequence of the GRN gene preventing translation [19, 20, 135, 136] or result in genomic deletion of one copy of the gene [137, 138].
The GRN R493X and T272fs mutations are among the most frequent mutations found in GRN patients [139, 140]. Patients carrying these mutations do not show significant phenotypic differences with other GRN mutation carriers. Interestingly, the occurrence of a founder effect has been suggested for both mutations [139, 141]. In addition, missense and silent mutations have been observed scattered along the GRN gene. For a large number of them, it is still debated if they play an active role in the disease pathogenesis. Some mutations are predicted to affect protein function in silico, they have been found in patients only, or experimental studies demonstrated a potential pathogenic effect causing reduced protein expression by cellular mechanisms other than GRN mRNA reduction [142, 143]. Mutations A9D, P248L, and R432C have been reported to affect protein secretion and stability thereby reducing the amount of available GRN. The A9D mutation [144] occurs within the hydrophobic core of the signal peptide sequence of GRN impairing its secretion. The mutated protein fails to undergo N-glycosylation, suggesting its missorting into the cytosol [135, 143]. The P248L and R432C mutations might contribute to disease phenotype by adversely affecting the neurotrophic properties of GRN [114].
GRN mutations pathologically confirmed in FTD with TDP-43 pathology are so far all heterozygote. The only exception is a single report of two siblings clinically diagnosed with adult-onset neuronal ceroid lipofuscinosis (NCL), a lysosomal storage disorder with severe accumulation of lipofuscin, and progressive neurodegeneration [145]. Interestingly, Grn−/− mice also show an increase of the aging pigment lipofuscin accompanied by tissue vacuolization in the hippocampus. Although we are still awaiting for the neuropathological assessment, the inclusion of GRN as genetic cause of NCL [146] has important consequences for the role of GRN in lysosome biology.
GRN Animal Models
To date, five independent Grn−/− mouse models have been established and extensively characterized (reviewed in [112, 147]). Although in humans GRN loss alone is sufficient to cause neurodegeneration, none of the mouse models fully recapitulate the human disease. Their most consistent behavioral phenotype is reduction in social interactions already observed at young age. Neuropathologically, Grn−/− mice all display pronounced progressive microgliosis and astrocytosis as well as ubiquitin accumulation in the cortex, hippocampus, thalamus, and brain stem. Accumulation of ubiquitinated proteins suggests disturbance of the proteasomal and/or autophagy-lysosomal pathways, which is supported by accumulation of the autophagy-related receptor p62 and increased expression of lysosomal protease cathepsin D [148]. Neuronal loss is in general not remarkable, and it is present only in selected areas; however, Grn−/− mice show impaired neuronal function with reduced synaptic connectivity and impaired synaptic plasticity. These findings support in part the results from GRN knockdown or knockout studies in primary hippocampal neuronal and slice cultures [149, 150]. Interestingly, altered synaptic vesicle numbers are also found in FTD patients carrying GRN mutations [149]. Grn−/− mice do not show TDP-43 fragmentation, cytoplasmic mislocalization, abnormal phosphorylation, and accumulation in aggregates typical of FTLD-TDP associated with GRN mutations [148, 151]. In the insoluble fraction of Grn−/− mice brain lysates, only full-length TDP-43 has been detected with a significant increase from 12 months forward. One study did show the appearance of phosphorylated TDP-43 in the cytosol of neurons in the hippocampal and thalamic areas [123, 152], and studies in mouse cortical neurons and GRN patient iPSC differentiated to neurons demonstrated increased translocation of TDP-43 from the nucleus to the cytoplasm [118, 121].
C9orf72
In 2011, two independent consortia identified the pathological expansion of a noncoding GGGGCC hexanucleotide repeat in C9orf72 as a cause of familial FTD and ALS, explaining several linkages and GWAS performed since 2006 linking chromosome 9p to these disorders [21, 22, 153, 154]. The findings where confirmed by other studies in a wide series of populations [155, 156], and repeat expansions for C9orf72 have since then also been confirmed in families affected with AD, CBS, and ataxia syndromes [157, 158].
The C9orf72 gene is transcribed in three major transcripts and located on the short arm of chromosome 9. The location of the repeat is between noncoding exons 1a and 1b, which is the first intron following noncoding exon 1 of transcript variants 1 and 3 and the upstream regulatory region of transcript variant 2 (Fig. 5.3). In the general population, the median length of the hexanucleotide repeat sequence is two repeats (range 0 to ±20). The C9orf72 transcript variants 1 and 3 encode for a 481 amino acid protein, whereas transcript variant 2 encodes for a shorter 222 amino acid protein. These protein isoforms share the first 221 N-terminal amino acids but differ in their C-terminal region. C9orf72 is detected throughout the CNS, with the highest expression level observed within the cerebellum [21, 22, 154, 159, 160]. Currently, there are no specific antibodies for C9orf72, and therefore, the exact subcellular localization is not very well established. In neuronal cell lines transfected with C9orf72, the protein is detected both in the nucleus and cytoplasm and in the medium [161], and additional studies have suggested C9orf72 is also present in the membrane fraction of cells after subcellular fractionation experiments [162, 163]. Further experiments are needed to conclusively determine where the protein is localized.
C9orf72 is highly conserved in evolution, and bioinformatics approaches showed that the protein is a novel homologue of differentially expressed in normal and neoplastic (DENN) proteins [164, 165]. DENN proteins are guanine exchange factors (GEF) that activate Rab GTPases, and these findings suggest a role for C9orf72 in Rab GTPase-dependent membrane trafficking. Support comes from a study in which several Rab proteins involved in endocytosis and autophagy were found to co-localize or co-immunoprecipitate with C9orf72 [161]. Knockdown of C9orf72 in neuronal cell lines also led to defects in autophagic processing as well as endocytosis. Furthermore, human neurons differentiated from iPSC with the C9orf72 repeat expansion were more sensitive to autophagy-inhibiting drugs [166]. Functional studies are required in order to conclusively demonstrate that C9orf72 encodes a GEF and Rab proteins might be activated.
Effect of the Pathogenic C9orf72 Mutation
The frequency of C9orf72 repeat expansions ranges from 12 to 25 % in familial and 6–7 % in sporadic FTD patients and 10–50 % in familial and 5–7 % in sporadic ALS cases. This makes C9orf72 repeat expansions the most common cause of the FTD/ALS complex of diseases [155, 167, 168]. The causal effect of the C9orf72 mutation is not yet completely understood, and currently, three mechanisms have been implicated for the disease.
There is accumulating evidence that the expanded repeat is associated with reduced expression of C9orf72 transcripts, and studies in human postmortem brain tissue, patient-derived iPSC, and lymphoblasts suggest that a loss of function might be relevant for the disease pathogenesis [21, 154, 159, 160, 162, 166, 169, 170]. Epigenetic changes could be responsible for the decrease in C9orf72 expression levels observed in patients, and this mechanism has been described previously for Friedreich’s ataxia and fragile X syndrome [171, 172]. This hypothesis is supported by two studies describing hypermethylation of CpG islands and abnormal histone binding associated with the repeat expansion [159, 173].
A second mechanism associated with repeat expansion diseases is RNA toxicity, caused by sequestration of normal transcripts and RNA-binding proteins by RNA molecules including the expanded repeat [174]. The presence of the expanded repeat in pre-mRNA transcripts could prevent normal splicing toward a mature mRNA, and the resulting repeat-containing RNA species could then aggregate into RNA foci and have a toxic effect. In support of this hypothesis, repeat-containing RNA aggregates have been reported in brains of patients and in patient-derived iPSC [21, 162, 163, 175, 176]. In vitro experiments using GGGGCC-repeat RNA oligonucleotides showed that they fold into stable RNA G-quadruplex structures, which suggests that the inclusion of the expanded repeat into the C9orf72 transcripts in vivo could interfere with the normal processing of the pre-mRNA for transcripts 1 and 3 [177, 178]. This is supported by in vitro transcription assays that show the presence of abortive transcripts caused by G-quadruplex assembly, and these findings were confirmed in patient-derived B lymphocytes [179]. There is also evidence for the sequestration of RNA-binding proteins (RBPs) by RNA molecules including the transcribed repeat expansion, which could cause a depletion of RBPs available for normal RNA metabolism. RNA-binding assays, using r(GGGGCC)10 repeat sequences, identified Pur α as a repeat binding protein. Loss of Pur α reduced cell viability of Neuro-2a cells and overexpression of Pur α in Drosophila, and Neuro-2a cells mitigated the repeat-mediated neurotoxicity [180]. The interaction of Pur α is supported by co-localization studies, and also binding of several heterogeneous nuclear ribonucleoprotein (hnRNP) family members to the hexanucleotide repeat has been reported [163, 181].
A third hypothesis is that repeat-associated non-ATG-initiated (RAN) translation takes place within the expanded repeat sequence, resulting in the production and aggregation of dipeptide repeat proteins. In support of this hypothesis, aggregates positively stained with antibodies raised against putative hexanucleotide repeat RAN-translated peptides have been detected in human postmortem brain and cultured patient-derived iPSC [162, 170, 182]. The presence of stable RNA G-quadruplex structures could induce RAN translation similar to what has been reported for expanded CAG repeats in spinocerebellar ataxia 8 and myotonic dystrophy type 1 [183]. Sequencing results of DNAse 1-treated pre-mRNA from postmortem tissue matched the C9orf72 genomic sequence and therefore support this hypothesis [182]. Interestingly, a C9orf72 antisense transcript containing intron 1 sequences including repeat sequences was detected raising the possibility that the dipeptide repeat proteins might be translated from this transcript [184]. Foci containing this antisense RNA transcript are observed in the same brain regions as sense foci, but they are present in fewer cells and the average number of foci per cell appears higher [175]. Recently, a study in U2OS cancer cells and human astrocytes showed that synthetic dipeptides containing 20 repeats of sense glycine-proline (GR) or antisense proline-arginine (PR) associate with nucleoli and affect cell morphology and viability. Exposure of cultured cells to these GR and PR translation products also led to altered pre-mRNA splicing and changes in ribosomal RNA biogenesis [185].
Animal Models for C9orf72
One of the first animal models created for C9orf72 was a zebrafish model in which the translation of the zC9orf72 orthologue was blocked using antisense morpholino oligonucleotides (AMO). This model system provided evidence that a decrease in C9orf72 expression level could be important for the disease process [169]. The knockdown resulted in disrupted branching and shortening of motor neuron axons when compared to noninjected or mismatch AMO-injected fish; this phenotype could be rescued by injecting the mRNA for the human C9orf72 long transcript. In addition, knockdown of C9orf72 in zebrafish resulted in motor deficits associated with axonopathy, such as deficits in touch-evoked escape response and reduced mobility. Partial knockdown of endogenous C9orf72 to 30–40 % of normal levels in a mouse model by antisense oligonucleotide administration was well tolerated for 18 weeks, which does not support that a loss of function is the main mechanism of the mutation [176]. Studies in patient fibroblasts and motor neurons derived from patient iPSC also did not confirm this hypothesis [163, 176]. A Drosophila model expressing the expanded hexanucleotide repeat (rGGGGCC) provides evidence that RNA foci or aberrantly processed pre-mRNAs are toxic. Neuronal toxicity in Drosophila and Neuro-2a cells was observed, and the expression of rGGGGCC repeats caused progressive neurodegeneration in Drosophila eye and a reduction in locomotor activity [180]. A more recent study differentiated between repeat RNA and DPR protein toxicity and showed that the major toxic species in their Drosophila model system are the DPR proteins; however, additional contribution of RNA toxicity is not ruled out [186].
VCP and CHMP2B
Mutations in two other genes, VCP and CHMP2B, lead to FTLD-TDP and account for a minority of familial cases [1]. Mutations in VCP were identified in 2004 by linkage analysis studies in families with inclusion body myopathy associated with Paget disease of bone and frontotemporal dementia (IBMPFD) [187]. VCP mutations are also a cause of familial ALS [188]. The protein is ubiquitously expressed and a highly conserved member of the AAA(+)-ATPase superfamily. The protein is associated with a wide variety of cellular activities, including cell cycle control and membrane fusion. It is also a multi-ubiquitin chain-targeting factor and is required in the degradation of many ubiquitin-proteasome pathway substrates [189]. IBMPFD mutations cluster in the N-terminal CDC48 domain, mediating substrate recognition and cofactor binding. Studies in patient tissue, transgenic mice, and cell models suggest that VCP is a key regulator at the intersection of autophagy and the ubiquitin-proteasome system [190, 191]. Mouse models expressing mutant VCP recapitulate aspects of the disease, including age-dependent degeneration in muscle, brain, and bone, and progressive widespread TDP-43 pathology [192, 193].
Mutations in CHMP2B were found in 2005 via linkage analysis in a large Danish FTD family [194], and mutations are also a cause of familial ALS [195]. The ubiquitinated neuronal cytoplasmic inclusions do not stain for tau, TDP-43, or FUS, and the classification is FTLD-UPS. CHMP2B is a component of the endosomal sorting complex required for transport III (ESCRT-III) and expressed in neurons of all major brain regions. The ESCRT-III complex is required for function of the multivesicular body (MVB), an endosomal structure that fuses with the lysosome to degrade endocytosed proteins. Mutations affect the C-terminal region of the protein due to aberrant splicing, and mutant CHMP2B disrupts the fusion of endosomes with lysosomes in cell culture models [196]. Mice expressing C-terminally truncated and mutant CHMP2B develop axonal swellings and have reduced survival. The mice also develop ubiquitinated protein inclusions negative for TDP-43 and FUS, mimicking the inclusions found in patients with CHMP2B mutations [197].
TARDBP and FUS
Mutations in TARDBP and FUS are found, although these are very rare in FTD and more common in ALS [24–27]. FTD associated with mutations in GRN, VCP, or C9orf72 is consistently characterized by the presence of TDP-43 pathology, and a considerable number of tau-/TDP-negative FTLD cases have inclusion of FUS, suggesting that dysregulation of both proteins might be important in the pathogenesis of FTD [10, 95].
TDP-43 is a 414 amino acid protein with two RNA recognition motifs and a carboxy-terminal glycine-rich domain, encoded by the TARDBP gene on chromosome 1. TDP-43 is a member of the hnRNP family of proteins and regulates RNA processing in a variety of ways. It is involved in mRNA transport, stability and turnover, splicing, and translation. The protein is highly conserved, is predominantly nuclear, and can shuttle between the nucleus and the cytoplasm [198–200]. Essentially, all ALS- and FTD-associated mutations are missense changes in the C-terminal glycine-rich region, involved in protein-protein interactions. In FTLD-TDP brains, TDP-43 is redistributed to the cytoplasm, hyperphosphorylated, ubiquitinated, and cleaved into the C-terminal fragments (CTFs) [95]. Experimental studies do not conclusively demonstrate whether TDP-43-mediated neurodegeneration results from a gain or loss of function of the protein. There is evidence for both: gains of functions mediated by aggregation and abnormal cytoplasmic function or loss of functions mediated by nuclear depletion, CTFs, and RNA dysregulation [201, 202].
FUS was first reported in 2009 to be the cause of ~3 % familial ALS cases and subsequently found to be the marker for the pathology of many remaining tau-/TDP-negative FTLD cases [10, 203, 204]. The FUS gene encodes a 526 amino acid protein and forms a gene family together with EWSR1 and TAF15 (FET). Increased insolubility of all FET proteins has been found in FTLD-FUS, but not in ALS-FUS [205]. It is highly conserved, ubiquitously expressed, and mainly localized to the nucleus. The protein has a high degree of functional homology with TDP-43 and is involved in multiple steps of RNA processing [206]. Most mutations are missense mutations affecting the C-terminus, disrupting the binding of FUS to Transportin. This nuclear import receptor shuttles proteins from the cytoplasm to the nucleus leading to an accumulation of mutant FUS in the cytoplasm [207]. Also for FUS, it is still unclear whether the cytosolic deposition causes loss of essential nuclear functions, a gain of toxic functions in the cytosol, or both.
Susceptibility Genes and Risk Loci
Compared to Mendelian FTD genes, little is known about susceptibility genes contributing to the risk of developing the disease. In 2010, Van Deerlin and colleagues identified TMEM106B in a genome-wide association study as a risk factor for FTLD-TDP [28]. Three SNPs encompassing the TMEM106B gene were found significant in a series of 515 FTLD-TDP patients, and variants specifically increased the risk in GRN mutation carriers. The initial GWAS finding has been successfully replicated in several FTD cohorts, strongly supporting a key role for TMEM106B in FTLD-TDP pathogenesis [208–210]. TMEMB106B is a 274 amino acid transmembrane type 2 protein with a highly glycosylated luminal domain [211]. It is cytoplasmically expressed in neurons, glia, and endothelial cells/pericytes of human brain samples from normal individuals, while in neurons of FTLD-TDP cases, TMEM106B appears to extend beyond the cell body into neuronal processes. In multiple immortalized cell lines and primary cortical neurons, TMEM106B is localized to late endosomes or lysosomes, and increased levels affect endolysosomal and progranulin pathways [212–214]. A recent GWAS points to novel associations, and the immune system processes, lysosomal, and autophagy pathways are potentially involved in FTD. The new loci need to be replicated in future studies to determine their possible association with the disease [29].
In 2011, UBQLN2 was added to the list of ALS-FTD genes [215]. The gene encodes the ubiquitin-like protein ubiquilin 2, a member of the ubiquitin family, which regulates the degradation of ubiquitinated proteins. In ~20 % of UBQLN2 mutation carriers, progressive dementia similar to FTD was identified, but all patients eventually developed motor symptoms. P62, encoded for by the SQSTM1 gene, is another protein at the intersection of ALS and FTD. It was found following the observation of involvement of P62 in ALS and has been subsequently reported in ALS and in FTD [216–218]. Inclusion positive for p62 can be found in C9orf72 expansion mutation patients, both with and without TDP-43 pathology [219].
Another risk factor for FTLD-TDP comes from a variant located in the 3′UTR of GRN in a binding site for the microRNA mir-659 [220]. In a series of pathologically confirmed FTLD-TDP patients without GRN mutations, Rademakers and colleagues observed that homozygous T-allele carriers had a 3.2-fold increase risk to develop FTLD-TDP as compared to homozygote C-allele carriers. They hypothesized that this variant reduces GRN protein expression through mir-659-dependent translational inhibition. It is still unclear whether GRN levels play a direct role in general FTLD population as two other studies failed to replicate the original findings [221, 222]. However, the risk allele is overrepresented in cases with hippocampal sclerosis [223, 224] and was found associated with a lower GRN serum level in two independent studies [225, 226], suggesting that decreased GRN expression may be a risk factor for FTLD-TDP and other dementias.
Conclusion
In recent years, remarkable progress has been made regarding the understanding of the genetic causes and neuropathological features of FTD. The recent discovery of the C9orf72 repeat expansions as the most common cause of the FTD/ALS complex of diseases showed that there is still a lot to be discovered. We know, for example, very little about susceptibility genes contributing to the risk of developing FTD and not all proteinopathies are fully characterized. The biological significance of the identified FTD genes has been studied extensively in cellular and animal models, as described in this chapter. However, diagnosis of FTD remains challenging, and no cure is available yet. Interestingly, many of the FTD genes seem to be connected at the molecular level. TMEM106B has originally been found as a risk factor for GRN mutation carriers, and several studies now describe TMEM106B as a genetic modifier for FTD with the C9orf72 repeat expansions [227, 228]. Patients with mutations in C9orf72 in combination with mutations in other genes involved in FTD/ALS have also been reported [229, 230]. Furthermore, FTD cases associated with GRN and C9orf72 mutations both present with TDP-43 pathology, and several studies showed that TDP-43 binds the 3′-UTR of GRN and regulates its expression [199, 231]. Understanding the full biology and connecting all identified FTD genes and risk factors with clinical phenotypes are of high importance for developing therapeutic approaches and offering reliable genetic advice to patients.
Abbreviations
- aFTLD-U:
-
Atypical frontotemporal lobar degeneration with ubiquitinated inclusions
- AGD:
-
Argyrophilic grain disease
- BIBD:
-
Basophilic inclusion body disease
- C9orf72 :
-
Chromosome 9 open reading frame 72
- CBD:
-
Corticobasal degeneration
- CHMP2B :
-
Charged multivesicular body protein 2B
- FTD-3:
-
Frontotemporal dementia linked to chromosome 3
- FTLD:
-
Frontotemporal lobar degeneration
- FUS :
-
Fused in sarcoma
- GRN :
-
Granulin
- MAPT :
-
Microtubule-associated protein tau
- MSTD:
-
Multiple system tauopathy with dementia
- NFT-dementia:
-
Neurofibrillary tangle predominant dementia
- ni:
-
No inclusions
- NIFID:
-
Neuronal intermediate filament inclusion disease
- PiD:
-
Pick’s disease
- PSP:
-
Progressive supranuclear palsy
- TARDBP :
-
TAR DNA-binding protein
- TDP:
-
TDP-43
- UPS:
-
Ubiquitin proteasome system
- VCP :
-
Valosin-containing protein
- WMT-GGI:
-
White matter tauopathy with globular glial inclusions
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Disclosure
Peter Heutink is a co-applicant on a patent application related to MAPT (PCT/US1999/009529) and C9orf72 (PCT/GB2012/052140) and is co-owner of Synaptologics BV.
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Heetveld, S., Rizzu, P., Heutink, P. (2015). Genetics of Frontotemporal Dementia. In: Schneider, S., Brás, J. (eds) Movement Disorder Genetics. Springer, Cham. https://doi.org/10.1007/978-3-319-17223-1_5
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