Mitochondrial defect and PGC-1α dysfunction in parkin-associated familial Parkinson's disease

Abstract

Mutations in the parkin gene are expected to play an essential role in autosomal recessive Parkinson's disease. Recent studies have established an impact of parkin mutations on mitochondrial function and autophagy. In primary skin fibroblasts from two patients affected by an early onset Parkinson's disease, we identified a hitherto unreported compound heterozygous mutation del exon2-3/del exon3 in the parkin gene, leading to the complete loss of the full-length protein. In both patients, but not in their heterozygous parental control, we observed severe ultrastructural abnormalities, mainly in mitochondria. This was associated with impaired energy metabolism, deregulated reactive oxygen species (ROS) production, resulting in lipid oxidation, and peroxisomal alteration. In view of the involvement of parkin in the mitochondrial quality control system, we have investigated upstream events in the organelles' biogenesis. The expression of the peroxisome proliferator-activated receptor gamma-coactivator 1-alpha (PGC-1α), a strong stimulator of mitochondrial biogenesis, was remarkably upregulated in both patients. However, the function of PGC-1α was blocked, as revealed by the lack of its downstream target gene induction. In conclusion, our data confirm the role of parkin in mitochondrial homeostasis and suggest a potential involvement of the PGC-1α pathway in the pathogenesis of Parkinson's disease. This article is part of a Special Issue entitled: Translating nuclear receptors from health to disease.

An active mitochondrial biogenesis occurs during dendritic cell differentiation

“…Absorbance change was recorded at 450 nm using a Victor X3 Multilabel Plate Readers. Catalase activity was assayed by monitoring spectrophotometrically the rate of decomposition of H 2 O 2 at 240 nm as previously described (Pacelli et al, 2011).…”

Parkinsonism Due to Mutations in PINK1, Parkin, and DJ-1 and Oxidative Stress and Mitochondrial Pathways

“…This would resolve the apparent contradictions in some of these models and may explain why the rescue of PINK1-deficiency phenotypes by parkin in flies is only a partial effect. This may also be related to observations of changes in PGC1a-responsive genes in fibroblasts from parkin mutation carriers (Pacelli et al 2011). Finally, if it is correct that there are many functional locations of parkin, we might surmise that the apparent lack of specificity of the protein may have evolved from a need to coordinate PINK1, Parkin, and DJ-1…”

Molecular Targets for Improvement of Parkinson's Disease Therapy

“…Investigations on transfected cell cultures has, however, provided evidence that parkin can also up-or down-regulate the expression of different genes [29]. Extensive investigation in the authors' laboratory in primary cultures of fibroblasts from patient's skin biopsies have shown that different mutations of PARK2, in independent patients affected by autosomal recessive PD, resulted in depression of mitochondrial respiratory chain enzymes, in particular complex I, inhibition of the mitochondrial respiratory activity and ATP production [30]. These effects were associated with defect in the PGC1□ mastered transcription cascade of mitochondrial respiratory proteins [30].…”

“…Extensive investigation in the authors' laboratory in primary cultures of fibroblasts from patient's skin biopsies have shown that different mutations of PARK2, in independent patients affected by autosomal recessive PD, resulted in depression of mitochondrial respiratory chain enzymes, in particular complex I, inhibition of the mitochondrial respiratory activity and ATP production [30]. These effects were associated with defect in the PGC1□ mastered transcription cascade of mitochondrial respiratory proteins [30]. Pathogenetic mutations in PARK6, coding for PINK1 serine/threonine kinase, represent the second most common cause of autosomal recessive PD.…”

“…A main target of Ca 2+ excitotoxicity is represented by mitochondria. Large accumulation of Ca 2+ in these organelles results in a deleterious cascade of events, which ultimately cause impairment of respiration and ATP production and enhancement of ROS production [30,44]. Impaired mitochondrial energy metabolism, oxidative stress conditions and age-related progressive accumulation of oxidatively damaged and misfolded proteins, which in turn aggregate and impair cellular house keeping and specialized functions, all together contribute to PD pathogenesis [45,46].…”