Genetic Architecture of MAPT Gene Region in Parkinson Disease Subtypes.

Esterina Pascale,Francesco Fattapposta,Alfonso Rubino,Giampiero Ferraguti,Marcella Valente,Giuseppe Meco,Maria Elena Di Battista,Carlo Purcaro

doi:10.3389/fncel.2016.00096

Esterina Pascale, Francesco Fattapposta + Show 6 more

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https://doi.org/10.3389/fncel.2016.00096

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Abstract

The microtubule-associated protein tau (MAPT) region has been conceptualized as a model of the interaction between genetics and functional disease outcomes in neurodegenerative disorders, such as Parkinson disease (PD). Indeed, haplotype-specific differences in expression and alternative splicing of MAPT transcripts affect cellular functions at different levels, increasing susceptibility to a range of neurodegenerative processes. In order to evaluate a possible link between MAPT variants, PD risk and PD motor phenotype, we analyzed the genetic architecture of MAPT in a cohort of PD patients. We observed a statistically significant association between the H1 haplotype and PD risk (79.5 vs 69.5%; χ2 = 9.9; OR, 1.7; 95% CI, 1.2–2.4; p = 0.002). The effect was more evident in non tremor dominant (TD) PD subjects (NTD-PD) (82 vs 69.5%; χ2 = 13.6; OR, 2.03; 95% CI, 1.4–3; p = 0.0003), while no difference emerged between PD subgroup of tremor dominant patients (TD-PD) and control subjects. Examination of specific intra-H1 variations showed that the H1h subhaplotype was overrepresented in NTD-PD patients compared with controls (p = 0.007; OR, 2.9; 95% CI, 1.3–6.3). Although we cannot exclude that MAPT variation may be associated with ethnicity, our results may support the hypothesis that MAPT H1 clade and a specific H1 subhaplotype influence the risk of PD and modulate the clinical expression of the disease, including motor phenotype.

Highlights

The microtubule-associated protein tau (MAPT) is a phosphorylated protein primarily expressed in the brain, where it assists in stabilization of the cytoskeleton and axonal transport in neurons
The association was greater in the Parkinson disease (PD) subgroup of nontremor dominant (NTD) patients compared with controls (82 vs. 69.5%; χ 2 = 13.6; odds ratio (OR), 2.03; 95% CI, 1.4–3; p = 0.0003) and remained significant after correction for multiple testing, while no statistically significant difference was disclosed between PD subgroup of tremor dominant (TD) patients and control subjects (72 vs. 69.5%; χ 2 = 0.17; OR, 1.1; 95% CI, 0.7–1.9; p = 0.7)
Among the other single nucleotide polymorphisms (SNP), only the rs3785883 was marginally statistical significant in the NTD-PD subgroup compared with control subjects (χ 2 = 4.3; OR, 1.5; 95% CI, 1.02–2.3; p = 0.044), but this difference did not remain significant after statistical correction considering the number of SNPs analyzed

Summary

Introduction

The microtubule-associated protein tau (MAPT) is a phosphorylated protein primarily expressed in the brain, where it assists in stabilization of the cytoskeleton and axonal transport in neurons. Inherited mutations in MAPT were formerly associated with forms of frontotemporal dementia and parkinsonism linked to chromosome 17, first providing evidence of a link between tau dysfunction and neurodegeneration (Hutton et al, 1998; Spillantini et al, 1998). The most common H1 haplotype has been linked to tauopathies such as Alzheimer’s disease (AD), progressive supranuclear palsy (PSP) and corticobasal degeneration (CBD; Myers et al, 2005; Pittman et al, 2006) and to the most common synucleinopathy such as Parkinson disease (PD), providing mostly positive albeit partially conflicting results (see Zabetian et al, 2007 for summary). The impact of H1 haplotype as a risk factor for PD has been confirmed in GWAS studies (Simón-Sánchez et al, 2009; Edwards et al, 2010) and meta-analysis by the PDGene forum (Lill et al, 2012)

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