A Proposed Mechanism for Neurodegeneration in Movement Disorders Characterized by Metal Dyshomeostasis and Oxidative Stress

Abstract

Shared molecular pathologies between distinct neurodegenerative disorders offer unique opportunities to identify common mechanisms of neuron death, and apply lessons learned from one disease to another. Neurotoxic superoxide dismutase 1 (SOD1) proteinopathy in SOD1-associated familial amyotrophic lateral sclerosis (fALS) is recapitulated in idiopathic Parkinson disease (PD), suggesting that these two phenotypically distinct disorders share an etiological pathway, and tractable therapeutic target(s). Despite 25 years of research, the molecular determinants underlying SOD1 misfolding and toxicity in fALS remain poorly understood. The absence of SOD1 mutations in PD highlights mounting evidence that SOD1 mutations are not the sole cause of SOD1 protein misfolding occasioning oligomerization and toxicity, reinforcing the importance of non-genetic factors, including protein metallation and post-translational modification in determining SOD1 stability and function. We propose that these non-genetic factors underlie the misfolding and dysfunction of SOD1 and other proteins in both PD and fALS, constituting a shared and tractable pathway to neurodegeneration.

Antioxidants and Nanotechnology: Promises and Limits of Potentially Disruptive Approaches in the Treatment of Central Nervous System Diseases

“…Even if the real causing mechanisms of Parkinson's disease are still under investigation, it seems that oxidative stress plays a central role in the neurodegeneration associated with the disease, being able to cause most of the cellular impairments typical of Parkinson's disease that, in turn, can lead to the generation of even more ROS in a self‐reinforcing cycle . Similarly to what we previously mentioned about Alzheimer's disease, the low level of antioxidant enzymatic activity like superoxide dismutase (SOD) or glutathione peroxidase (GPx) observed in Parkinson's disease patients seems to confirm the link between oxidative stress and the disease . Currently, there are no treatments able to revert the neurodegeneration of the dopaminergic neurons, and the gold standard in Parkinson's disease treatment is still the use of 3,4‐dihydroxy‐ l ‐phenylalanine ( l ‐DOPA) .…”

“…Similarly to what we described concerning Alzheimer's disease, it is not clear whether oxidative stress is a cause of Parkinson's disease or rather a consequence of other cellular impairments. For example, we discussed the role of mitochondrial dysfunction in Parkinson's disease pathogenesis, but mithocondria are not only producer of ROS, yet also one of the main targets of oxidative stress‐induced damage . It has been demonstrated that α‐synuclein aggregation is affected by elevated ROS levels .…”

“…For example, we discussed the role of mitochondrial dysfunction in Parkinson's disease pathogenesis, but mithocondria are not only producer of ROS, yet also one of the main targets of oxidative stress‐induced damage . It has been demonstrated that α‐synuclein aggregation is affected by elevated ROS levels . and even the cellular clearance pathways like the ubiquitin–proteasome system (UPS) can be impaired by high levels of ROS .…”

Lipid-derived electrophiles induce covalent modification and aggregation of Cu,Zn-superoxide dismutase in a hydrophobicity-dependent manner

“…These two regions (dimer interface -loop IV and the electrostatic loop -loop VII) are frequently affected by genetic and non-genetic factors, the later including an array of posttranslational modifications (PTM, e.g. acylation, sumoylation, ubiquitination, glycation) 67,68 . Dimer interface modifications have been shown to enhance monomer formation 69 , increasing the production of high molecular weight inclusions 70 .…”

On elucidation of the role of mitochondria dysfunction and oxidative stress in multiple sclerosis

“…As an example, many neurotransmitters have been implicated in MS. Glutamate excitotoxicity has been implicated in MS. 214,215 Research indicates that MtD plays an important role in glutamate-induced neuronal excitotoxicity, 216 by impacting upon the ability of the neuron to resist excitotoxic stress. 217,218 Glutamate excitotoxicity induces OS 219 and glutamate excitotoxicity is in part driven by the failure of antioxidant mechanisms to preserve cellular redox homeostasis. 220 OS modulates the uptake of GABA and glutamate 221 and plays a role in glutamate excitotoxicity.…”