Abstract
Accumulation of protein aggregates is the leading cause of cellular dysfunction in neurodegenerative disorders. Alzheimer’s disease (AD), Parkinson’s disease (PD), Huntington’s disease, Prion disease and motor disorders such as amyotrophic lateral sclerosis, present with a similar pattern of progressive neuronal death, nervous system deterioration and cognitive impairment. The common characteristic is an unusual misfolding of proteins which is believed to cause protein deposition and trigger degenerative signals in the neurons. A similar clinical presentation seen in many neurodegenerative disorders suggests the possibility of shared neuronal responses in different disorders. Despite the difference in core elements of deposits in each neurodegenerative disorder, the cascade of neuronal reactions such as activation of glycogen synthase kinase-3 beta, mitogen-activated protein kinases, cell cycle re-entry and oxidative stress leading to a progressive neurodegeneration are surprisingly similar. This review focuses on protein toxicity in two neurodegenerative diseases, AD and PD. We reviewed the activated mechanisms of neurotoxicity in response to misfolded beta-amyloid and α-synuclein, two major toxic proteins in AD and PD, leading to neuronal apoptosis. The interaction between the proteins in producing an overlapping pathological pattern will be also discussed.
Highlights
Protein misfolding and aggregation contribute to the pathophysiology of neurodegenerative disorders such as Alzheimer’s (AD) and Parkinson’s diseases (PD)
GSK3 is modulated through a variety of pathways including wnt, phosphatidylinositide-3 kinase (PI3K) and Akt deactivate glycogen synthase kinase-3 Beta (GSK-3β) by phosphorylating Ser9 [58, 59], increasing GSK-3β, in pre-tangles which is closely associated with tangle-bearing neurons suggesting a role in tau hyperphosphorylation in Alzheimer’s disease (AD) [60,61,62,63,64]
It has been shown that instead of immediate cell death, affected neurons live for several months in a near- functional state [209, 210]. Constant production of both proteins allows continuing protein–protein interaction and as a result, a reciprocal induction between α-Syn and Aβ could cause a gradual increase in the protein levels of Conclusion the process of neuronal death is a common feature in AD and PD, the underlying mechanisms are still under investigation
Summary
Protein misfolding and aggregation contribute to the pathophysiology of neurodegenerative disorders such as Alzheimer’s (AD) and Parkinson’s diseases (PD). The plaques are the consequences of abnormal protein folding and aggregation with direct and indirect toxic effects on neuronal survival [14, 15]. AD patients appear to produce abundant extracellular Aβ, resulting in plaque formation with a high level of toxicity causing extensive neuronal apoptosis [55,56,57].
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