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

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.

Tau hyperphosphorylation and deregulation of calcineurin in mouse models of Huntington's disease.

Huntington's disease (HD) is an autosomal-dominant neurodegenerative disorder caused by polyglutamine expansions in the amino-terminal region of the huntingtin (Htt) protein. At the cellular level, neuronal death is accompanied by the proteolytic cleavage, misfolding and aggregation of huntingtin. Abnormal hyperphosphorylation of tau protein is a characteristic feature of a class of neurodegenerative diseases called tauopathies. As a number of studies have reported tau pathology in HD patients, we investigated whether HD pathology may promote tau hyperphosphorylation and if so tackle some of its underlying mechanisms. For that purpose, we used the R6/2 mouse, a well-characterized model of HD, and analyzed tau phosphorylation before and after the onset of HD-like symptoms. We found a significant increase in tau hyperphosphorylation at the PHF-1 epitope in pre-symptomatic R6/2 mice, whereas symptomatic mice displayed tau hyperphosphorylation at multiple tau phosphoepitopes (AT8, CP13, PT205 and PHF-1). There was no activation of major tau kinases that could explain this observation. However, when we examined tau phosphatases, we found that calcineurin/PP2B was downregulated by 30% in pre-symptomatic and 50% in symptomatic R6/2 mice, respectively. We observed similar changes in tau phosphorylation and calcineurin expression in Q175 mice, another HD model. Calcineurin was also reduced in Q111 compared with Q7 cells. Finally, pharmacological or genetic inhibition of endogenous calcineurin was sufficient to promote tau hyperphosphorylation in neuronal cells. Taken together, our data suggest that mutant huntingtin can induce abnormal tau hyperphosphorylation in vivo, via the deregulation of calcineurin.

The effect of striatal pre-enkephalin overexpression in the basal ganglia of the 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine mouse model of Parkinson's disease.

The midbrain dopamine (DA) cell death underlying Parkinson's disease (PD) is associated with upregulation of pre-enkephalin (pENK) in striatopallidal neurons. Our previous results obtained with 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP) parkinsonian monkeys suggest that increased striatal expression of pENK mRNA is a compensatory mechanism to alleviate PD-related motor symptoms. In this study, we tested the hypothesis that increased pENK expression in the striatum protects against the neurotoxic insults of MPTP in mice. To this end, recombinant adeno-associated virus serotype 2 also containing green fluorescent protein was used to overexpress pENK prior to DA depletion. Our results showed that overexpression of pENK in the striatum of MPTP mice induced: (i) increased levels of the opioid peptide enkephalin (ENK) in the striatum; (ii) higher densities of ENK-positive fibers in both the globus pallidus (GP) and the substantia nigra; (iii) higher locomotor activity; and (iv) a higher density of striatal tyrosine hydroxylase-positive fibers in the striatum. In addition, striatal overexpression of pENK in MPTP -treated mice led to 52 and 43% higher DA concentrations and DA turnover, respectively, in the GP compared to sham-treated MPTP mice. These observations are in agreement with the idea that increased expression of pENK at an early stage of disease can improve PD symptoms.