Mitochondrial PINK1–PARK2 problem may promote PD

Abstract

Experiments with drosophila suggest that mutation of the human PINK1 gene could lead to Parkinson’s disease (PD) via the impairment of mitochondrial function (Nature 2006, published online May 3. DOI:10.1038/ nature04779 and DOI:10.1038/ nature04788). These fi ndings, released by two independent groups, add to the growing evidence that mitochondrial dysfunction is central to the development of Parkinson’s disease. “Mutations in PINK1 and parkin [PARK2] have been associated with familial, early onset and sporadic forms of PD”, explains Ming Guo (University of California, Los Angeles, USA). “In addition, PD has been linked to mitochondrial dysfunction since exposure to mitochondrial toxins leads to PD-like pathology. The observations reported in these two new papers help link all this together by showing that mutations in pink1, the drosophila analogue of human PINK1, can lead to mitochondrial dysfunction and even the degeneration of dopaminergic neurones.” Guo’s team generated drosophila pink1-deletion strains and examined the morphology of their mitochondria (where the pink1 product localises). The energy-intensive fl ight muscles were disorganised and the mitochondrial cristae either fragmented or virtually absent. “These muscle problems were degenerative in nature since they were not appreciable when the fl ies fi rst hatched”, explains Guo. In further experiments the team also showed that the pink1-deletion mutants were more sensitive to free radicals. The inability to tolerate free radicals is a known problem of mitochondrial dysfunction—and free radical damage has been associated with PD, further linking the disease to PINK1 mutations in human beings. In independent work, researchers led by Jongkyeong Chung (Korea Advanced Institute of Science and Technology, Taejon, Korea) obtained similar results. Their drosophila pink1 mutants also had fl ightmuscle defects, a probable result of the marked reduction in their mitochondrial DNA load. Importantly, Chung’s team also saw evidence of mitochondrial dysfunction in the dopaminergic neurons of Pink1 mutant brains. “Since dopaminergic neurodegeneration is the most critical issue in Parkinson’s disease, we examined the morphology of the mitochondria in dopaminergic neurons using TEM and [via the expression of green fl uorescent protein]”, explains Chung. Many were enlarged, a condition that seemed to correlate with both reduced dopamine concentrations and neurodegeneration; adult pink1 mutant fl ies showed a 10% loss of dopaminergic neurons. “It therefore seems likely that human PINK1 is involved in maintaining mitochondrial integrity: without it the mitochondria become dysfunctional, leading to a range of factors linked to PD.” Both teams also report pink1 and parkin almost certainly belong to the same pathway. Parkin overexpression compensated for the lack of pink1, suggesting that the product of pink1 functions upstream of parkin. Doug Turnbull (University of Newcastle, UK), commented: “Working out the full pathway via which PINK1 and parkin are involved in maintaining mitochondrial integrity might show a point where we could act to halt mitochondrial breakdown and hopefully help us prevent and treat PD—at least in patients with mutations in these genes.”