Rare mutations in the gene encoding for tau (MAPT, microtubule-associated protein tau) cause frontotemporal dementia-spectrum (FTD-s) disorders, including FTD, progressive supranuclear palsy (PSP) and corticobasal syndrome, and a common extended haplotype spanning across the MAPT locus is associated with increased risk of PSP and Parkinson's disease. We identified a rare tau variant (p.A152T) in a patient with a clinical diagnosis of PSP and assessed its frequency in multiple independent series of patients with neurodegenerative conditions and controls, in a total of 15 369 subjects. Tau p.A152T significantly increases the risk for both FTD-s (n = 2139, OR = 3.0, CI: 1.6-5.6, P = 0.0005) and Alzheimer's disease (AD) (n = 3345, OR = 2.3, CI: 1.3-4.2, P = 0.004) compared with 9047 controls. Functionally, p.A152T (i) decreases the binding of tau to microtubules and therefore promotes microtubule assembly less efficiently; and (ii) reduces the tendency to form abnormal fibers. However, there is a pronounced increase in the formation of tau oligomers. Importantly, these findings suggest that other regions of the tau protein may be crucial in regulating normal function, as the p.A152 residue is distal to the domains considered responsible for microtubule interactions or aggregation. These data provide both the first genetic evidence and functional studies supporting the role of MAPT p.A152T as a rare risk factor for both FTD-s and AD and the concept that rare variants can increase the risk for relatively common, complex neurodegenerative diseases, but since no clear significance threshold for rare genetic variation has been established, some caution is warranted until the findings are further replicated.
"The possibility of multiple mutations contributing to ALS in one individual,12 and the role of rare variants in complex diseases such as ALS and FTD, remains to be elucidated and will require very large cohorts in order to obtain sufficiently convincing results. Recently, Geschwind and collaborators have shown that a rare variant in the MAPT gene, where mutations are known to be causative for FTD, can act as a risk factor for FTD and Alzheimer's disease.13 Similarly, we here suggest that a rare variant in PFN1, a gene in which mutations are known to be causative for ALS, can act as a risk factor for disease. "
[Show abstract][Hide abstract] ABSTRACT: Amyotrophic lateral sclerosis (ALS) and frontotemporal dementia (FTD) are progressive neurodegenerative disorders that share significant clinical, pathological and genetic overlap and are considered to represent different ends of a common disease spectrum. Mutations in Profilin1 have recently been described as a rare cause of familial ALS. The PFN1 E117G missense variant has been described in familial and sporadic cases, and also found in controls, casting doubt on its pathogenicity. Interpretation of such variants represents a significant clinical-genetics challenge.
Here, we combine a screen of a new cohort of 383 ALS patients with multiple-sequence datasets to refine estimates of the ALS and FTD risk associated with PFN1 E117G. Together, our cohorts add up to 5118 ALS and FTD cases and 13 089 controls. We estimate a frequency of E117G of 0.11% in controls and 0.25% in cases. Estimated odds after population stratification is 2.44 (95% CI 1.048 to ∞, Mantel-Haenszel test p=0.036).
Our results show an association between E117G and ALS, with a moderate effect size.
Journal of neurology, neurosurgery, and psychiatry 12/2013; 85(5). DOI:10.1136/jnnp-2013-306761 · 6.81 Impact Factor
"There was also immunoreactivity in a subset of Lewy bodies, similar to the pattern we previously noted with other antibodies to phospho-tau . T149 and T153 are largely unexplored tau epitopes, but it is of interest that they flank a rare variant in tau, A152T, that may be a risk factor for tauopathies such as PSP [7, 34, 36]. LRRK2 is not known to play a role in tauopathies beyond its involvement in PD, but it is possible that rare genetic variants in LRRK2, including those that confer risk to PD [16, 60, 62] or have yet to be uncovered, could play a role in tauopathies. "
[Show abstract][Hide abstract] ABSTRACT: Mutations in the gene encoding leucine-rich repeat kinase 2 (LRRK2) are the most frequent cause of familial Parkinson’s disease (PD). The neuropathology of LRRK2-related PD is heterogeneous and can include aberrant tau phosphorylation or neurofibrillary tau pathology. Recently, LRRK2 has been shown to phosphorylate tau in vitro; however, the major epitopes phosphorylated by LRRK2 and the physiological or pathogenic consequences of these modifications in vivo are unknown. Using mass spectrometry, we identified multiple sites on recombinant tau that are phosphorylated by LRRK2 in vitro, including pT149 and pT153, which are phospho-epitopes that to date have been largely unexplored. Importantly, we demonstrate that expression of transgenic LRRK2 in a mouse model of tauopathy increased the aggregation of insoluble tau and its phosphorylation at T149, T153, T205, and S199/S202/T205 epitopes. These findings indicate that tau can be a LRRK2 substrate and that this interaction can enhance salient features of human disease.
Electronic supplementary material
The online version of this article (doi:10.1007/s00401-013-1188-4) contains supplementary material, which is available to authorized users.
"The novel MAPT variant identified in our case is located in a region of the protein far from microtubule-binding domains and does not have an obvious role in the molecule's function. A similar variant was also recently reported in exon 7 of the MAPT gene (Coppola et al., 2012; Cruchaga et al., 2012; Jin et al., 2012; Kara et al., 2012), and a rare variant p.A239T in exon 8 (NM_005910.5) was found in a carrier of a C9orf72 repeat expansion (King et al., 2013) (Fig. 1). Interestingly, these 3 rare variants all localize in an uncharacterized region of the MAPT protein in cases with unexpected tau pathology, which supports the speculation that these variants may have a disease-modifying role and may predispose the individual to tau pathology (Coppola et al., 2012; Devine and Lewis, 2008; Gan-Or et al., 2012; Kara et al., 2012). "
[Show abstract][Hide abstract] ABSTRACT: Leucine-rich repeat kinase 2 (LRRK2) mutation is the most common cause of genetic-related parkinsonism and is usually associated with Lewy body pathology; however, tau, α-synuclein, and ubiquitin pathologies have also been reported. We report the case of a patient carrying the LRRK2 G2019S mutation and a novel heterozygous variant c.370C>G, p.Q124E in exon 4 of the microtubule-associated protein tau (MAPT). The patient developed parkinsonism with good levodopa response in her 70s. Neuropathological analysis revealed nigral degeneration and Alzheimer-type tau pathology without Lewy bodies. Immunohistochemical staining using phospho-TDP-43 antibodies identified occasional TDP-43 pathology in the hippocampus, temporal neocortex, striatum, and substantia nigra. However, TDP-43 pathology was not identified in another 4 archival LRRK2 G2019S cases with Lewy body pathology available in the Queen Square Brain Bank. Among other published cases of patients carrying LRRK2 G2019S mutation, only 3 were reportedly evaluated for TDP-43 pathology, and the results were negative. The role of the MAPT variant in the clinical and pathological manifestation in LRRK2 cases remains to be determined.
Neurobiology of aging 05/2013; 34(12). DOI:10.1016/j.neurobiolaging.2013.04.011 · 5.01 Impact Factor
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