Mitochondrial Dysfunction andα-Synuclein Synaptic Pathology in Parkinson’s Disease: Who’s on First?

Abstract

Parkinson's disease (PD) is the most common neurodegenerative movement disorder. Its characteristic neuropathological features encompass the loss of dopaminergic neurons of the nigrostriatal system and the presence of Lewy bodies and Lewy neurites. These are intraneuronal and intraneuritic proteinaceous insoluble aggregates whose main constituent is the synaptic protein α-synuclein. Compelling lines of evidence indicate that mitochondrial dysfunction and α-synuclein synaptic deposition may play a primary role in the onset of this disorder. However, it is not yet clear which of these events may come first in the sequel of processes leading to neurodegeneration. Here, we reviewed data supporting either that α-synuclein synaptic deposition precedes and indirectly triggers mitochondrial damage or that mitochondrial deficits lead to neuronal dysfunction and α-synuclein synaptic accumulation. The present overview shows that it is still difficult to establish the exact temporal sequence and contribution of these events to PD.

Mitochondrial dysfunction and mitophagy defect triggered by heterozygous GBA mutations

“…The loss of GBA activity promotes SNCA accumulation by inhibiting lysosomal function, whereas direct interactions between mutant GBA and SNCA promote SNCA aggregation [71]. Additionally, impaired mitochondrial homeostasis may interact with SNCA deposition to form a ‘vicious cycle’, in which SNCA accumulation increases mitochondrial permeability [72,73] and mitochondrial ROS generation, which further promotes SNCA misfolding, aggregation, and accumulation [73]. We propose that, as a predisposing factor, heterozygous GBA mutations may contribute to the risk of PD by conferring a distinct subclinical pathological state with mitochondrial dysfunction and autophagy defects, which lowers the threshold and increases the risk for SNCA accumulation, ultimately culminating in the development of PD.…”

Antioxidant Activity of Oral Administration of Rosmarinus Officinalis Leaves Extract on Rat's Hippocampus which Exposed to 6-Hydroxydopamine

“…Accumulation of iron in substantia nigra contributes to the cell death by enhancing lipid peroxidation, as judged by raised levels of both malondialdehyde and lipid hydroperoxides (Hauser et al 2013;Ward et al 2015). But the hippocampus is the most vulnerable area to oxidative stress, it was demonstrated that an early event in the course of dopamine depletion following 6-OHDA administration is the generation of oxidative stress in the hippocampus and it caused memory impairment (Hritcu et al 2011;Sriraksa et al 2012;Zaltieri et al 2015). The post-mortem studies from PD patients suggested the involvement of an excess formation of free radicals and the onset of oxidative stress in the disease progression (Ren et al 2009).…”

Adverse Outcome Pathway on binding of agonists to ionotropic glutamate receptors in adult brain leading to excitotoxicity that mediates neuronal cell death, contributing to learning and memory impairment

“…• A build up of toxic proteins in the brain (Lansbury et al, 2006;Majd et al, 2015;Zaltieri et al, 2015) • A loss of mitochondrial function that leads to the oxidative stress and creation of neurotoxic molecules that trigger cell death (apoptotic, necrotic or autophagy) Betarbet et al,2000;Zhu and Chu, 2010) • Changes in the levels and activities of neurotrophic factors (Zuccato and Cattaneo, 2009;Michalski et al, 2015) • Variations in the activity of neural networks Kann, 2015;Sala-Llonch et al, 2014).…”

“…However, the causative link between mitochondrial dysfunction and its relationship to protein degradation and intracellular transport is well documented (Zaltieri et al, 2015). The dynamic nature of protein aggregation means that, despite progress towards understanding aggregation, its relationship to disease is difficult to determine in the laboratory.…”

“…Dysfunction of mitochondria induces oxidative stress, production of free radicals, calcium overload, and mutations in mitochondrial DNA that contribute to neurodegenerative diseases. In all major examples of neurodegenerative diseases there is strong evidence that mitochondrial dysfunction occurs early and acts causally in disease pathogenesis (Zaltieri et al, 2015). Moreover, an impressive number of disease-specific proteins interact with mitochondria.…”