Identification of common variants influencing risk of the tauopathy progressive supranuclear palsy

Department of Neurology, Philipps-Universität, Marburg, Germany.
Nature Genetics (Impact Factor: 29.35). 07/2011; 43(7):699-705. DOI: 10.1038/ng.859
Source: PubMed

ABSTRACT Progressive supranuclear palsy (PSP) is a movement disorder with prominent tau neuropathology. Brain diseases with abnormal tau deposits are called tauopathies, the most common of which is Alzheimer's disease. Environmental causes of tauopathies include repetitive head trauma associated with some sports. To identify common genetic variation contributing to risk for tauopathies, we carried out a genome-wide association study of 1,114 individuals with PSP (cases) and 3,247 controls (stage 1) followed by a second stage in which we genotyped 1,051 cases and 3,560 controls for the stage 1 SNPs that yielded P ≤ 10(-3). We found significant previously unidentified signals (P < 5 × 10(-8)) associated with PSP risk at STX6, EIF2AK3 and MOBP. We confirmed two independent variants in MAPT affecting risk for PSP, one of which influences MAPT brain expression. The genes implicated encode proteins for vesicle-membrane fusion at the Golgi-endosomal interface, for the endoplasmic reticulum unfolded protein response and for a myelin structural component.

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    • "Both types of mutations result in glial tangles and/or neurofibrillary tangles. Also, common genetic variations in the MAPT genomic region increase risk for developing progressive supranuclear palsy7,8 and Parkinson's disease.9 Thus, altered tau protein or its regulation can cause neurodegeneration. "
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    ABSTRACT: In Alzheimer's disease, progressive supranuclear palsy, and a number of other neurodegenerative diseases, the microtubule associated protein tau aggregates to form intracellular neurofibrillary tangles and glial tangles, abnormal structures that are part of disease pathogenesis. Disorders with aggregated tau are called tauopathies. Presently, there are no disease-modifying treatments for this disease class. Tau is encoded by the MAPT gene. We propose that reducing MAPT expression and thus the amount of tau protein made could prevent aggregation, and potentially be an approach to treat tauopathies. We tested 31 morpholinos, complementary to the sense strand of the MAPT gene to identify oligonucleotides that can downregulate MAPT expression and reduce the amount of tau protein produced. Oligonucleotides were tested in human neuroblastoma cell lines SH-SY5Y and IMR32. We identified several morpholinos that reduced MAPT mRNA expression up to 50% and tau protein levels up to ~80%. The two most potent oligonucleotides spanned the 3' boundary of exons 1 and 5, masking the 5'-splice sites of these exons. Both morpholinos induced skipping of the targeted exons. These in vitro findings were confirmed in mice transgenic for the entire human MAPT gene and that express human tau protein. These studies demonstrate the feasibility of using modified oligonucleotides to alter tau expression.
    Molecular Therapy - Nucleic Acids 07/2014; 3(7):e180. DOI:10.1038/mtna.2014.30 · 4.51 Impact Factor
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    • "In both PSP and CBD, the possession of H1 allele of the MAPT gene and, in particular, the H1/H1 genotype is a risk factor which was also detected in both the patient and his older brother [40,41]. Although PSP and CBD are sporadic conditions, there have been reports of familial aggregation of parkinsonism in PSP [42] and a recent genome-wide association study (GWAS) identified variants within several loci increasing the risk for PSP [43]. Interestingly, Apo E4 allele frequency is lower in PSP than in controls [43,44]. "
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    ABSTRACT: We report the case of a 75-year-old ex-professional boxer who developed diplopia and eye movement abnormalities in his 60's followed by memory impairment, low mood and recurrent falls. Examination shortly before death revealed hypomimia, dysarthria, vertical supranuclear gaze palsy and impaired postural reflexes. Pathological examination demonstrated 4-repeat tau neuronal and glial lesions, including tufted astrocytes, consistent with a diagnosis of progressive supranuclear palsy. In addition, neurofibrillary tangles composed of mixed 3-repeat and 4-repeat tau and astrocytic tangles in a distribution highly suggestive of chronic traumatic encephalopathy were observed together with limbic TDP-43 pathology. Possible mechanisms for the co-occurrence of these two tau pathologies are discussed.
    02/2014; 2(1):24. DOI:10.1186/2051-5960-2-24
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    • "Schellenberg and colleagues recently completed a genome-wide association study (GWAS) for PSP risk loci [10]. One of the genes identified was eukaryotic translation initiation factor 2 alpha kinase 3 (EIF2AK3), which encodes the protein pancreatic endoplasmic reticulum kinase (PERK). "
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    ABSTRACT: Progressive supranuclear palsy (PSP) is a neurodegenerative disorder pathologically characterized by intracellular tangles of hyperphosphorylated tau protein distributed throughout the neocortex, basal ganglia, and brainstem. A genome-wide association study identified EIF2AK3 as a risk factor for PSP. EIF2AK3 encodes PERK, part of the endoplasmic reticulum's (ER) unfolded protein response (UPR). PERK is an ER membrane protein that senses unfolded protein accumulation within the ER lumen. Recently, several groups noted UPR activation in Alzheimer's disease (AD), Parkinson's disease (PD), amyotrophic lateral sclerosis, multiple system atrophy, and in the hippocampus and substantia nigra of PSP subjects. Here, we evaluate UPR PERK activation in the pons, medulla, midbrain, hippocampus, frontal cortex and cerebellum in subjects with PSP, AD, and in normal controls. We found UPR activation primarily in disease-affected brain regions in both disorders. In PSP, the UPR was primarily activated in the pons and medulla and to a much lesser extent in the hippocampus. In AD, the UPR was extensively activated in the hippocampus. We also observed UPR activation in the hippocampus of some elderly normal controls, severity of which positively correlated with both age and tau pathology but not with Aβ plaque burden. Finally, we evaluated EIF2AK3 coding variants that influence PERK activation. We show that a haplotype associated with increased PERK activation is genetically associated with increased PSP risk. The UPR is activated in disease affected regions in PSP and the genetic evidence shows that this activation increases risk for PSP and is not a protective response.
    07/2013; 1(1):31. DOI:10.1186/2051-5960-1-31
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