Genetic reduction of mitochondrial complex I function does not lead to loss of dopamine neurons in vivo.

Inhibition of mitochondrial complex I activity is hypothesized to be one of the major mechanisms responsible for dopaminergic neuron death in Parkinson's disease. However, loss of complex I activity by systemic deletion of the Ndufs4 gene, one of the subunits comprising complex I, does not cause dopaminergic neuron death in culture. Here, we generated mice with conditional Ndufs4 knockout in dopaminergic neurons (Ndufs4 conditional knockout mice [cKO]) to examine the effect of complex I inhibition on dopaminergic neuron function and survival during aging and on 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP) treatment in vivo. Ndufs4 cKO mice did not show enhanced dopaminergic neuron loss in the substantia nigra pars compacta or dopamine-dependent motor deficits over the 24-month life span. These mice were just as susceptible to MPTP as control mice. However, compared with control mice, Ndufs4 cKO mice exhibited an age-dependent reduction of dopamine in the striatum and increased α-synuclein phosphorylation in dopaminergic neurons of the substantia nigra pars compacta. We also used an inducible Ndufs4 knockout mouse strain (Ndufs4 inducible knockout) in which Ndufs4 is conditionally deleted in all cells in adult to examine the effect of adult onset, complex I inhibition on MPTP sensitivity of dopaminergic neurons. The Ndufs4 inducible knockout mice exhibited similar sensitivity to MPTP as control littermates. These data suggest that mitochondrial complex I inhibition in dopaminergic neurons does contribute to dopamine loss and the development of α-synuclein pathology. However, it is not sufficient to cause cell-autonomous dopaminergic neuron death during the normal life span of mice. Furthermore, mitochondrial complex I inhibition does not underlie MPTP toxicity in vivo in either cell autonomous or nonautonomous manner. These results provide strong evidence that inhibition of mitochondrial complex I activity is not sufficient to cause dopaminergic neuron death during aging nor does it contribute to dopamine neuron toxicity in the MPTP model of Parkinson's disease. These findings suggest the existence of alternative mechanisms of dopaminergic neuron death independent of mitochondrial complex I inhibition.

Tau phosphorylation in Alzheimer's disease: potential involvement of an APP-MAP kinase complex.

The two predominant pathological concomitants of Alzheimer's disease (AD) are senile plaques and neurofibrillary tangles. Although many biochemical studies have addressed the composition and formation of these AD hallmarks, very little is known about the interrelationship between the two. Here we present evidence that the tau phosphorylation characteristic of neurofibrillary tangles may be mediated by a physical association of MKK6 (mitogen-associated protein kinase kinase 6) with tau and subsequent phosphorylation of tau by the MKK6 substrate, p38 MAPK; and that APP (beta-amyloid precursor protein) may be co-immunoprecipitated both with MKK6 and its upstream MAPKKK, ASK1. Taken together with recent data demonstrating APP dimerization by beta-amyloid peptide (Abeta) (Lu et al., 2003), and the possible activation of ASK1 via APP dimerization (Hashimoto et al., 2003), these results suggest a model of AD in which Abeta peptide dimerizes APP directly, leading to the activation of ASK1, MKK6, and p38, with subsequent phosphorylation of tau at sites characteristic of AD.