Genetics and Molecular Biology of Alzheimer’s Disease and Frontotemporal Lobar Degeneration
pairs into the intron following the first non-coding exon of the GRN gene (IVS0+5G-C). This is predicted to prevent splicing out of intron 0, leading the messenger RNA (mRNA) to be retained within the nucleus and subjected to nuclear degradation.64
At present there is no obvious
mechanistic link between the mutations in MAPT and GRN, currently assuming that their proximity on chromosome 17 is simply a coincidence. Progranulin is known by several different names, including granulin, acrogranin, epithelin precursor, proepithelin, and prostate cancer (PC)-cell-derived growth factor.65
The protein is
encoded by a single gene on chromosome 17q21 that produces a 593-amino-acid, cysteine-rich protein with a predicted molecular weight of 68.5kDa. The full-length protein is subjected to proteolysis by elastase, and this process is regulated by a secretory leukocyte protease inhibitor (SLPI).66
Progranulin and the various granulin
peptides are implicated in a range of biological functions including development, wound repair and inflammation by activating signalling cascades that control cell-cycle progression and cell motility.65
Excess
progranulin appears to promote tumour formation and hence can act as a cell survival signal. Despite the increasing literature on the function of progranulin, its role in neuronal function and survival remains unclear. In the human brain, GRN is expressed in neurons but significantly is also highly expressed in activated microglia,63
with
the result that GRN expression is increased in many neuro- degenerative diseases.
Since the original identification of null mutations in FTLD in 2006, numerous novel mutations have been reported, spanning most exons, and to date 68 GRN mutations have been described (
www.molgen.ua.ac.be/).
The majority of mutations identified create functional null alleles, causing premature termination of the GRN coding sequence. This leads to the degradation of the mutant RNA by non-sense-mediated decay, creating a null allele.63,64
The presence of a null mutation causes
a partial loss of functional progranulin protein, which in turn leads eventually to neurodegeneration (haploinsufficency mechanism), although how loss of GRN causes neuronal cell death remains unclear. Estimates of the frequency of GRN mutations in typical FTD patient populations suggests that they account for about 5–10% of all FTD cases, although numbers vary markedly depending on the nature of the populations considered.64,67,68
Neuropathology analysis has revealed that ubiquitin immunoreactive neuronal cytoplasmatic and intranuclear inclusions were present in all cases with FTDP-17 where pathological findings were available.69 Furthermore, soon after the identification of mutations in GRN, biochemical analyses demonstrated that truncated and hyper- phosphorylated isoforms of the TAR-DNA binding protein (TDP-43) are major components of the ubiquitin-positive inclusions in families with GRN mutations as well as in idiopathic FTD and a proportion of amyotrophic lateral sclerosis (ALS) cases.70
TDP-43 is a ubiquitously
expressed and highly conserved nuclear protein that can act as a transcription repressor, an activator of exon skipping or a scaffold for nuclear bodies through interactions with survival motor neuron protein. Under pathological conditions, TDP-43 has been shown to relocate from the neuronal nucleus to the cytoplasm, a consequence of which may be the loss of TDP-43 nuclear functions.70
The
mechanism by which loss of progranulin leads to TDP-43 accumulation and whether this is necessary for neurodegeneration in this group of diseases remain to be clarified.
EUROPEAN NEUROLOGICAL REVIEW
Sporadic Frontotemporal Lobar Degeneration The most well-known risk factor for late-onset AD, Apo E4, has also been considered as a risk factor for sporadic FTLD. A number of studies have suggested an association between FTLD and the APOE*4 allele.80–85 However, other authors did not replicate these data.86–88
Recent findings
demonstrated an association between the APOE*4 allele and FTLD in males but not females,89
previously reported. An increased frequency of the APOE*4 allele was described in patients with SD compared with those with FTD and PA.87
15 possibly explaining the discrepancies
In conclusion, the function of progranulin in the brain is currently unclear; why loss of this protein leads to neurodegenerative diseases in mid-life remains to be established, and its possible role as a regulator of repair activity in the central nervous system, as is well known to occur in periphery, remains a challenge for science. The gene encoding for TDP-43, named TARDBP, has been extensively studied and a number of mutations found in its C-terminal glycine- rich region. Unexpectedly, the clinical phenotype of carriers was ALS, and aggregates made of TDP-43 have been described in the brain and spinal cord of such patients.71
A recently published collaborative study72 analysed GRN in a
population of 434 patients with FTLD, including FTD, PA, SD, FTD/ALS, FTD/motor neurone disease (MND), corticobasal degeneration (CBD) and progressive supranuclear palsy (PSP). Fifty-eight variants were identified, including 24 pathogenic variants. The frequency of GRN mutations was 6.9% of all FTLD-spectrum cases, 21.4% of cases with a pathological diagnosis of FTLD-U, 16% of FILD-spectrum cases with a family history of a similar neurodegenerative disease and 56.2% of cases of FTLD-U with a family history. Clinical information was available for 31 GRN mutation-positive patients from 28 different families. The most common clinical diagnosis was FTD (n=24); three patients were diagnosed with PA, three with AD and one with CBD. The majority of GRN mutations introduced a premature termination codon, suggesting that their corresponding mRNA will be degraded through non-sense-mediated decay, supporting the hypothesis that most GRN mutations create a functional null allele.72
Two additional genes have been shown to cause FTLD. In 1995 Brown et al.73
It consists of a mutation in the splice
reported linkage to the pericentromeric region of chromosome 3 in a large multigenerational family with FTLD from Denmark. Nevertheless, the aberrant gene in this family has only recently been identified.74
acceptor site of exon 6 of charged multivescicular body protein 2B (CHMP2B), which is part of the endosomal ESCRTIII complex. The change from G to C results in an alteration of the splice acceptor site of exon 6, causing aberrant mRNA splicing of this transcript, which leads to the insertion of 201 base pairs of the intron between exons 5 and 6. In addition, a further transcript was identified, resulting from the use of a cryptic splice site consisting of 10 base pairs from the 5’ end of exon 6. In any case, mutations in CHMP2B appear as a rare genetic cause of FTLD mainly due to their rare frequency of occurrence, showing moreover that the CHMP2B locus does not increase the risk of FTLD.75
Lastly, the first evidence of linkage with chromosome 9q21-22 comes from a study carried out in families with MND and FTD.76
Despite the
evidence of linkage to chromosome 9q21-22 in several additional FTD-MND families, the gene responsible for the disease in this locus has yet to be identified.77–79
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