Cellular and Molecular Basis of Neurodegeneration in Parkinson Disease

Alzheimer disease (AD) and Parkinson disease (PD) are the two most common age-related neurodegenerative diseases characterized by prominent neurodegeneration in selective neural systems. Although a small fraction of AD and PD cases exhibit evidence of heritability, among which many genes have been identified, the majority are sporadic without known causes. Molecular mechanisms underlying neurodegeneration and pathogenesis of these diseases remain elusive. Convincing evidence demonstrates oxidative stress as a prominent feature in AD and PD and links oxidative stress to the development of neuronal death and neural dysfunction, which suggests a key pathogenic role for oxidative stress in both AD and PD. Notably, mitochondrial dysfunction is also a prominent feature in these diseases, which is likely to be of critical importance in the genesis and amplification of reactive oxygen species and the pathophysiology of these diseases. In this review, we focus on changes in mitochondrial DNA and mitochondrial dynamics, two aspects critical to the maintenance of mitochondrial homeostasis and function, in relationship with oxidative stress in the pathogenesis of AD and PD. Copyright © 2012 Elsevier Inc. All rights reserved.

Antigen presentation is essential for establishing immune tolerance and for immune responses against infectious disease and cancer. Although antigen presentation can be mediated by autophagy, here we demonstrate a pathway for mitochondrial antigen presentation (MitAP) that relies on the generation and trafficking of mitochondrial-derived vesicles (MDVs) rather than on autophagy/mitophagy. We find that PINK1 and Parkin, two mitochondrial proteins linked to Parkinson's disease (PD), actively inhibit MDV formation and MitAP. In absence of PINK1 or Parkin, inflammatory conditions trigger MitAP in immune cells, both in vitro and in vivo. MitAP and the formation of MDVs require Rab9 and Sorting nexin 9, whose recruitment to mitochondria is inhibited by Parkin. The identification of PINK1 and Parkin as suppressors of an immune-response-eliciting pathway provoked by inflammation suggests new insights into PD pathology.

Parkinson's disease (PD) is a movement disorder that is characterized by the progressive degeneration of dopaminergic neurons in substantia nigra pars compacta resulting in dopamine deficiency in the striatum. Although majority of the PD cases are sporadic several genetic mutations have also been linked to the disease thus providing new opportunities to study the pathology of the illness. Studies in humans and various animal models of PD reveal that mitochondrial dysfunction might be a defect that occurs early in PD pathogenesis and appears to be a widespread feature in both sporadic and monogenic forms of PD. The general mitochondrial abnormalities linked with the disease include mitochondrial electron transport chain impairment, alterations in mitochondrial morphology and dynamics, mitochondrial DNA mutations and anomaly in calcium homeostasis. Mitochondria are vital organelles with multiple functions and their dysfunction can lead to a decline in energy production, generation of reactive oxygen species and induction of stress-induced apoptosis. In this review, we give an outline of mitochondrial functions that are affected in the pathogenesis of sporadic and familial PD, and hence provide insights that might be valuable for focused future research to exploit possible mitochondrial targets for neuroprotective interventions in PD. Copyright © 2013 Elsevier Ltd. All rights reserved.