Mitochondrial dysfunction has long been suspected to play a key role in neurodegeneration in Parkinson's disease. PINK1 and Parkin, the products of two genes responsible for autosomal recessive Parkinsonian syndromes with early onset, act as a quality control system on the outer mitochondrial membrane to preserve mitochondrial integrity. While doing so, they interact with multiple molecular actors in processes regulating mitochondrial biology and cell survival. The physiological conditions that mobilize these processes in neurons, and the mechanisms underlying their integration and spatiotemporal coordination, remain to be elucidated. Understanding how dysfunction of these house-keeping pathways leads to the preferential degeneration of a specific neuronal population in Parkinson's disease is a major challenge for future research.
Data provided are for informational purposes only. Although carefully collected, accuracy cannot be guaranteed. The impact factor represents a rough estimation of the journal's impact factor and does not reflect the actual current impact factor. Publisher conditions are provided by RoMEO. Differing provisions from the publisher's actual policy or licence agreement may be applicable.
"). PINK1 and parkin have been shown to maintain mitochondrial quality control (Corti and Brice, 2013). While the precise biological function of DJ-1 is unknown, it is known to respond to oxidative stress and defend against mitochondrial damage (Wilson, 2011). "
[Show abstract][Hide abstract] ABSTRACT: Mutations in the DJ-1 gene cause autosomal recessive parkinsonism in humans. Several mouse models of DJ-1 deficiency have been developed, but they do not have dopaminergic neuron cell death in the substantia nigra pars compacta (SNpc). Mitochondrial DNA (mtDNA) damage occurs frequently in the aged human SNpc but not in the mouse SNpc. We hypothesized that the reason DJ-1-deficient mice do not have dopaminergic cell death is due to an absence of mtDNA damage. We tested this hypothesis by crossing DJ-1-deficient mice with mice that have similar amounts of mtDNA damage in their SNpc as aged humans (Polg mutator mice). At 1 year of age, we counted the amount of SNpc dopaminergic neurons in the mouse brains using both colorimetric and fluorescent staining followed by unbiased stereology. No evidence of dopaminergic cell death was observed in DJ-1-deficient mice with the Polg mutator mutation. Furthermore, we did not observe any difference in dopaminergic terminal immunostaining in the striatum of these mice. Finally, we did not observe any changes in the amount of GFAP-positive astrocytes in the SNpc of these mice, indicative of a lack of astrogliosis. Altogether, our findings demonstrate the DJ-1-deficient mice, Polg mutator mice, and DJ-1-deficient Polg mutator mice have intact nigrastriatal pathways. Thus, the lack of mtDNA damage in the mouse SNpc does not underlie the absence of dopaminergic cell death in DJ-1-deficient mice.
"In healthy mitochondria, PINK1 translocates to the IMM via the TOMM20 machinery, where it is cleaved and rapidly degraded by the mitochondrial inner membrane rhomboid protease presenilinassociated rhomboid-like protease (Jin et al., 2010; Meissner et al., 2011) as well as other mitochondrial proteases MMP, m-AAA and ClpXP (Van Laar & Berman, 2013). In damaged mitochondria, when the membrane potential is lowered, mitochondrial import of PINK1 by the TOMM machinery is inhibited, resulting in accumulation of full-length PINK1 on the OMM (Corti & Brice, 2013) where it plays a pivotal role in the removal of damaged mitochondria from the cell (Becker et al., 2012; Song et al., 2013). "
"Indeed most autosomal recessive forms were found to be caused by the alteration of a gene encoding a protein localized to mitochondria, either in particular contexts, as in the case of Parkin  and DJ-1 , or constitutively for PINK1 . Furthermore, studies in various models and from many independent laboratories have provided evidence for interaction between the PARK2 and PINK1 genes and their protein products in a common pathway centered on maintenance of mitochondrial quality . In cell models Parkin and PINK1 regulate the elimination of dysfunctional mitochondria through mitophagy –. "
[Show abstract][Hide abstract] ABSTRACT: Loss of Parkin, encoded by PARK2 gene, is a major cause of autosomal recessive Parkinson's disease. In Drosophila and mammalian cell models Parkin has been shown in to play a role in various processes essential to maintenance of mitochondrial quality, including mitochondrial dynamics, biogenesis and degradation. However, the relevance of altered mitochondrial quality control mechanisms to neuronal survival in vivo is still under debate. We addressed this issue in the brain of PARK2-/- mice using an integrated mitochondrial evaluation, including analysis of respiration by polarography or by fluorescence, respiratory complexes activity by spectrophotometric assays, mitochondrial membrane potential by rhodamine 123 fluorescence, mitochondrial DNA content by real time PCR, and oxidative stress by total glutathione measurement, proteasome activity, SOD2 expression and proteins oxidative damage. Respiration rates were lowered in PARK2-/- brain with high resolution but not standard respirometry. This defect was specific to the striatum, where it was prominent in neurons but less severe in astrocytes. It was present in primary embryonic cells and did not worsen in vivo from 9 to 24 months of age. It was not associated with any respiratory complex defect, including complex I. Mitochondrial inner membrane potential in PARK2-/- mice was similar to that of wild-type mice but showed increased sensitivity to uncoupling with ageing in striatum. The presence of oxidative stress was suggested in the striatum by increased mitochondrial glutathione content and oxidative adducts but normal proteasome activity showed efficient compensation. SOD2 expression was increased only in the striatum of PARK2-/- mice at 24 months of age. Altogether our results show a tissue-specific mitochondrial defect, present early in life of PARK2-/- mice, mildly affecting respiration, without prominent impact on mitochondrial membrane potential, whose underlying mechanisms remain to be elucidated, as complex I defect and prominent oxidative damage were ruled out.