Proteinopathy, oxidative stress and mitochondrial dysfunction: cross talk in Alzheimer's disease and Parkinson's disease

Abstract

Alzheimer’s disease and Parkinson’s disease are two common neurodegenerative diseases of the elderly people that have devastating effects in terms of morbidity and mortality. The predominant form of the disease in either case is sporadic with uncertain etiology. The clinical features of Parkinson’s disease are primarily motor deficits, while the patients of Alzheimer’s disease present with dementia and cognitive impairment. Though neuronal death is a common element in both the disorders, the postmortem histopathology of the brain is very characteristic in each case and different from each other. In terms of molecular pathogenesis, however, both the diseases have a significant commonality, and proteinopathy (abnormal accumulation of misfolded proteins), mitochondrial dysfunction and oxidative stress are the cardinal features in either case. These three damage mechanisms work in concert, reinforcing each other to drive the pathology in the aging brain for both the diseases; very interestingly, the nature of interactions among these three damage mechanisms is very similar in both the diseases, and this review attempts to highlight these aspects. In the case of Alzheimer’s disease, the peptide amyloid beta (Aβ) is responsible for the proteinopathy, while α-synuclein plays a similar role in Parkinson’s disease. The expression levels of these two proteins and their aggregation processes are modulated by reactive oxygen radicals and transition metal ions in a similar manner. In turn, these proteins – as oligomers or in aggregated forms – cause mitochondrial impairment by apparently following similar mechanisms. Understanding the common nature of these interactions may, therefore, help us to identify putative neuroprotective strategies that would be beneficial in both the clinical conditions.

Icariside II, a Phosphodiesterase-5 Inhibitor, Attenuates Beta-Amyloid-Induced Cognitive Deficits via BDNF/TrkB/CREB Signaling

“…As it is expected, ICS II mitigated Aβ-induced neuronal death through inhibiting PDE5 and regulating Caspase 3, consistent with previous findings in vivo [5]. Furthermore, several studies revealed that oxidative stress is the redox state resulting from an imbalance between the generation and detoxification of ROS, and it is known to play an important role in the [30]. Aggravation of Aβ promotes ROS overproduction and excessive ROS accelerates the neurotoxicity of Aβ in turn [31].…”

A mitochondrial FUNDC1/HSC70 interaction organizes the proteostatic stress response at the risk of cell morbidity

“…This senescent phenotype seems to depend on the mitochondrial accumulation of proteasomal client substrates. Thus, mitochondrial accumulation of unfolded proteins, rather than MAPA formation, is probably responsible for the occurrence of cell senescence, in agreement with the fact that even monomeric aggregation-prone proteins are toxic to mitochondria and cells (Ganguly et al, 2017). The effects of these molecules on cell senescence were highly correlated with their effects on the mitochondrial accumulation of proteasomal clients.…”

Aβ exacerbates α‐synuclein‐induced neurotoxicity through impaired insulin signaling in α‐synuclein‐overexpressed human SK‐N‐MC neuronal cells

“…All these supported that attenuated AMPK activation and impaired insulin signaling may act as a detecting factor representing an underlying mechanism of αSyn pathology. On the other hand, evidence suggesting that oxidative stress elicited by mitochondrial dysfunction may be involved in the process of αSyn‐induced neurotoxicity . Particularly, in vitro studies have shown that increasing levels of oxidative stress can lead to αSyn aggregation .…”