Evidence for a role of the rare p.A152T variant in MAPT in increasing the risk for FTD-spectrum and Alzheimer's diseases.
ABSTRACT 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.
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ABSTRACT: Abnormal phosphorylation ("hyperphosphorylation") and aggregation of Tau protein are hallmarks of Alzheimer disease and other tauopathies but their causative connection is still a matter of debate. Tau with Alzheimer-like phosphorylation is also present in hibernating animals, mitosis or during embryonic development, without leading to pathophysiology or neurodegeneration. Thus the role of phosphorylation and the distinction between physiological and pathological phosphorylation needs to be further refined. So far the systematic investigation of highly phosphorylated Tau was difficult since a reliable method of preparing reproducible quantities was not available. Here we generated full-length Tau (2N4R) in Sf9 cells in a well-defined phosphorylation state containing up to ~20 phosphates as judged by mass spectrometry and western blotting with phospho-specific antibodies. In spite of the high concentration in living Sf9 cells (estimated ~ 230 uM) and high phosphorylation the protein was not aggregated. However, after purification the highly phosphorylated protein readily formed oligomers, whereas fibrils were observed only rarely. Exposure of mature primary neuronal cultures to oligomeric phospho-Tau caused reduction of spine density on dendrites but did not change the overall cell viability.Journal of Biological Chemistry 10/2014; 289(49). DOI:10.1074/jbc.M114.611368 · 4.60 Impact Factor
Article: Genetics of Alzheimer's disease.[Show abstract] [Hide abstract]
ABSTRACT: Alzheimer's disease (AD) represents the main form of dementia, and is a major public health problem. Despite intensive research efforts, current treatments have only marginal symptomatic benefits and there are no effective disease-modifying or preventive interventions. AD has a strong genetic component, so much research in AD has focused on identifying genetic causes and risk factors. This chapter will cover genetic discoveries in AD and their consequences in terms of improved knowledge regarding the disease and the identification of biomarkers and drug targets. First, we will discuss the study of the rare early-onset, autosomal dominant forms of AD that led to the discovery of mutations in three major genes, APP, PSEN1, and PSEN2. These discoveries have shaped our current understanding of the pathophysiology and natural history of AD as well as the development of therapeutic targets and the design of clinical trials. Then, we will explore linkage analysis and candidate gene approaches, which identified variants in Apolipoprotein E (APOE) as the major genetic risk factor for late-onset, "sporadic" forms of AD (LOAD), but failed to robustly identify other genetic risk factors, with the exception of variants in SORL1. The main focus of this chapter will be on recent genome-wide association studies that have successfully identified common genetic variations at over 20 loci associated with LOAD outside of the APOE locus. These loci are in or near-novel AD genes including BIN1, CR1, CLU, phosphatidylinositol-binding clathrin assembly protein (PICALM), CD33, EPHA1, MS4A4/MS4A6, ABCA7, CD2AP, SORL1, HLA-DRB5/DRB1, PTK2B, SLC24A4-RIN3, INPP5D, MEF2C, NME8, ZCWPW1, CELF1, FERMT2, CASS4, and TRIP4 and each has small effects on risk of AD (relative risks of 1.1-1.3). Finally, we will touch upon the ongoing effort to identify less frequent and rare variants through whole exome and whole genome sequencing. This effort has identified two novel genes, TREM2 and PLD3, and shown a role for APP in LOAD. The identification of these recently identified genes has implicated previously unsuspected biological pathways in the pathophysiology of AD.
Article: Genomics in Neurological Disorders[Show abstract] [Hide abstract]
ABSTRACT: Neurological disorders are a variety of complex diseases in the central nervous system, which can be roughly classified as neurodegenerative diseases and psychiatric disorders. The basic and translational research of neurological disorders has been hindered by the difficulty in accessing the pathological center (i.e., the brain) in live patients. The rapid advancement of sequencing and array technologies has made it possible to investigate the disease mechanism and biomarkers from a systems perspective. In this review, recent progresses in the discovery of novel risk genes, treatment targets and peripheral biomarkers employing genomic technologies will be discussed. Our major focus will be on two of the most heavily investigated neurological disorders, namely Alzheimer’s disease and autism spectrum disorder.Genomics Proteomics & Bioinformatics 08/2014; DOI:10.1016/j.gpb.2014.07.002