The toxin MPTP generates similar cognitive and locomotor deficits in hTau and tau knock-out mice

Highlights

• Tau protein does not contribute to cognitive and locomotor deficits induced by MPTP.

• MPTP injections decrease soluble and insoluble tau fractions in hTau mice brain.

• Decreased tau correlates with the loss of dopaminergic neurons in the brainstem.

Abstract

Parkinson’s disease (PD) is characterized by motor deficits, although cognitive disturbances are frequent and have been noted early in the disease. The main pathological characteristics of PD are the loss of dopaminergic neurons and the presence of aggregated α-synuclein in Lewy bodies of surviving cells. Studies have also documented the presence of other proteins within Lewy bodies, particularly tau, a microtubule-associated protein implicated in a wide range of neurodegenerative diseases, including Alzheimer’s disease (AD). In AD, tau pathology correlates with cognitive dysfunction, and tau mutations have been reported to lead to dementia associated with parkinsonism. However, the role of tau in PD pathogenesis remains unclear. To address this question, we induced parkinsonism by injecting the toxin 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP) in hTau mice, a mouse model of tauopathy expressing human tau, and a mouse model knock-out for tau (TKO). We found that although MPTP impaired locomotion (gait analysis) and cognition (Barnes maze), there were no discernable differences between hTau and TKO mice. MPTP also induced a slight but significant increase in tau phosphorylation (Thr205) in the hippocampus of hTau mice, as well as a significant decrease in the soluble and insoluble tau fractions that correlated with the loss of dopaminergic neurons in the brainstem. Overall, our findings suggest that, although MPTP can induce an increase in tau phosphorylation at specific epitopes, tau does not seem to causally contribute to cognitive and locomotor deficits induced by this toxin.

Introduction

Neurodegenerative diseases share a number of pathological features including cell degeneration accompanied by the accumulation of various pathological peptides or proteins such as β-amyloid, tau, α-synuclein etc. Parkinson’s disease (PD), which is characterized primarily by the loss of dopaminergic neurons within the nigro-striatal pathway, is no exception. The resulting dopamine depletion leads to some of the most prominent motor dysfunctions this condition is known for, which include bradykinesia, rigidity and tremors (Fahn, 2003, Olanow et al., 2009). However, cell loss is not restricted to these structures and, as the disease progresses, other systems are targeted. Notably, the disease is characterized by the presence of Lewy bodies (LB); nuclear inclusions mainly composed of the protein α-synuclein (Baba et al., 1998, Spillantini et al., 1997).

It has recently emerged that other pathological proteins such as tau, which has been suggested to underlie impairments of cognitive functions in Alzheimer’s disease (AD) (Arriagada et al., 1992, Bretteville and Planel, 2008, Duff and Planel, 2005), may also play a role in PD (Zhang et al., 2018). In addition to LB, neurofibrillary tangles, which are formed of hyperphosphorylated tau, have been observed in PD brains (Bancher et al., 1993, Joachim et al., 1987). In particular, tau is present within filaments of LB and has been shown to co-localize with α-synuclein (Arima et al., 1999, Ishizawa et al., 2003). Remarkably, several genome-wide association studies in PD subjects of European descent have revealed an association between the MAPT locus and PD risk (Edwards et al., 2010, Pankratz et al., 2009, Simon-Sanchez et al., 2009). Mutations in MAPT, the gene responsible for producing tau proteins, has also been identified in familial frontotemporal dementia with parkinsonism linked to chromosome 17 (FTDP-17) (Hutton et al., 1998, Lee et al., 2001). Cognitive impairments are commonly diagnosed in parkinsonian patients (Owen et al., 1997, Watson and Leverenz, 2010) and have been documented to occur from the early stages of disease evolution (Lewis et al., 2003).

Despite emerging evidence, the role of tau in PD pathogenesis remains unclear. In this study, we investigated whether the administration of the toxin 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP), classically used as a model of PD by generating subtle dopaminergic degeneration, altered motor and cognitive behaviours in mice knock-out for tau (TKO) or mice expressing the human tau protein (hTau). Our study aimed to dissect the impact of MPTP-induced parkinsonism in locomotor and cognitive behavioural aspects in relation to tau or phosphorylated tau levels.