Mechanisms of mitochondrial quality control in autosomal recessive Parkinson's disease.

Olga Corti

doi:10.1186/2193-1801-4-s1-l36

Abstract

The genes encoding the E3 ubiquitin protein ligase Parkin (PARK2) and the mitochondrial serine/threonine kinase PINK1 (PARK6) are mutated in clinically similar, autosomal recessive early onset Parkinson’s disease (PD) forms. Over the past ten years, a number of studies in different model systems have demonstrated that PINK1 and Parkin regulate jointly several processes relevant to maintenance of mitochondrial quality, including mitochondrial trafficking and dynamics, mitophagy and biogenesis. By using a combination of approaches of cell biology, confocal imaging and biochemistry in different cell models, we recently showed that loss of protein import efficiency triggers recruitment of Parkin by PINK1 in proximity of the translocase of outer mitochondrial membrane (TOM). We provided evidence that the degradation of specific TOM subunits plays a key role in initiating the autophagic degradation of damaged mitochondria. We also showed that PINK1 and Parkin interact with the TOM machinery on polarized mitochondria. Our results suggests that this interaction modulates the import of the multifunctional mitochondrion-protective matrix enzyme 17beta-hydroxysteroid dehydrogenase 10, which is depleted in Parkin-deficient mice and Parkinson’s disease patients. Electron and confocal microscopy, and calcium imaging approaches used to characterize the endoplasmic reticulum (ER)-mitochondria interface, a compartment previously linked to neurodegenerative processes, revealed enhanced juxtaposition between these organelles, associated with increased ER-to-mitochondria calcium transfer in cells from Parkin-deficient mice and patients with PARK2 mutations. Our current work aims at investigating the relevance of mitochondrial quality control mechanisms regulated by PINK1 and Parkin in different cell types of the central nervous system, to evaluate the contribution of each of them to the physiopathology of autosomal recessive Parkinson’s disease.

Highlights

Alzheimer’s disease (AD) is an incurable neurodegenerative disease characterized by progressive dementia
The results of the present study indicate that development of the neuronal hypoxic tolerance induced by the three-trial, in contrast to one-trial, mild hypoxic preconditioning is apparently largely associated with the activation of CREB, as well as brain-derived neurotrophic factor (BDNF) and Bcl-2 overexpression
No significant differences in serum level of Solubile form of RAGE (sRAGE) where found between rapidly progressing and slow progressing subgroup of multiple sclerosis (MS) patients.Our results suggest for the role of sRAGE in MS ethiopathogenesis, but we did not find any association of sRAGE in serum with the rate of MS disability progression

Summary

Introduction

Alzheimer’s disease (AD) is an incurable neurodegenerative disease characterized by progressive dementia. The aim of the study was to characterize the effects of streptozocin (STZ)-indced diabetes on learning and memory of 5XFAD and wild-type (WT) mice in Morris water maze (MWM) at ages 2 and 6 months and on brain amyloid load. Existing evidence suggests GABAergic system is involved in pathophysiology of Alzheimer’s disease (AD) via inhibitory interneuron deficits (Verret et al, 2012) and decrease in functional GABAA receptors (Limon et al, 2012). Our concept: low doses of muscimol may prevent learning/memory deficits in intracerebroventricular (icv) streptozocin (STZ)-induced AD nontransgenic rat model. The Sigma-1 receptor is a chaperone protein that modulates intracellular calcium signalling of the endoplasmatic reticulum and is involved in learning and memory processes.The aim of the present study was to compare in vitro Ca2+ concentration modulating activity and in vivo behavioural effects of enantiomers of methylphenylpiracetam, a novel positive allosteric modulator of Sigma-1 receptors

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