The microtubule-associated protein tau is thought to play a pivotal role in neurodegeneration. Mutations in the tau coding gene MAPT are a cause of frontotemporal dementia, and the H1/H1 genotype of MAPT, giving rise to higher tau expression levels, is associated with progressive supranuclear palsy, corticobasal degeneration, and Parkinson disease (PD). Furthermore, tau hyperphosphorylation and aggregation is a hallmark of Alzheimer disease (AD), and reducing endogenous tau has been reported to ameliorate cognitive impairment in a mouse model for AD. Tau hyperphosphorylation and aggregation have also been described in amyotrophic lateral sclerosis (ALS), both in human patients and in the mutant SOD1 mouse model for this disease. However, the precise role of tau in motor neuron degeneration remains uncertain.
The possible association between ALS and the MAPT H1/H2 polymorphism was studied in 3,540 patients with ALS and 8,753 controls. Furthermore, the role of tau in the SOD1G93A mouse model for ALS was studied by deleting Mapt in this model.
The MAPT genotype of the H1/H2 polymorphism did not influence ALS susceptibility (odds ratio = 1.08 [95% confidence interval 0.99–1.18], p = 0.08) and did not affect the clinical phenotype. Lowering tau levels in the SOD1G93A mouse failed to delay disease onset (p = 0.302) or to increase survival (p = 0.557).
These findings suggest that the H1/H2 polymorphism in MAPT is not associated with human amyotrophic lateral sclerosis, and that lowering tau levels in the mutant SOD1 mouse does not affect the motor neuron degeneration in these animals.
|AD||= Alzheimer disease;|
|ALS||= amyotrophic lateral sclerosis;|
|ANOVA||= analysis of variance;|
|CI||= confidence interval;|
|hAPP||= human amyloid precursor protein;|
|CBD||= corticobasal degeneration;|
|eGFP||= enhanced green fluorescent protein;|
|FTD||= frontotemporal dementia;|
|MAPT||= microtubule-associated protein tau;|
|OR||= odds ratio;|
|PD||= Parkinson disease;|
|PSP||= progressive supranuclear palsy;|
|SNP||= single nucleotide polymorphism;|
|SOD1||= superoxide dismutase 1.|