Alpha-synuclein and beta-amyloid – different targets, same players: calcium, free radicals and mitochondria in the mechanism of neurodegeneration

Abstract

Two of the most devastating neurodegenerative diseases are consequences out of misfolding and aggregation of key proteins-alpha synuclein and beta-amyloid. Although the primary targets for the two proteins are different, they both share a common mechanism that involves formation of pore-like structure on the plasma membrane, consequent dysregulation of calcium homeostasis, mitochondrial dysfunction and oxidative damage. The combined effect of all this factors ultimately leads to neuronal cell death. Whereas beta amyloid acts on the astrocytic plasma membrane, exhibiting a tight dependence to the membrane cholesterol content, alpha-synuclein does not distinguish between type of membrane or cell. Additionally, oligomeric forms of both proteins produce reactive oxygen species through different mechanisms: beta-amyloid through activation of the NADPH oxidase and alpha-synuclein through non-enzymatic way. Finally, both peptides in oligomeric form induce mitochondrial depolarisation through calcium overload and free radical production that ultimately lead to opening of the mitochondrial permeability transition pore and trigger cell death.

Protein misfolding in neurodegenerative diseases: implications and strategies

“…That is, the relationship between the accumulation of misfolded disease proteins and other signs of cellular distress is bidirectional, and in many cases mutually exacerbating. For example, amyloid-β, a-synuclein, and mHtt all cause acute oxidative stress in neurons and/or astrocytes, and impair astroglial anti-oxidant responses [37–40]. Conversely, oxidative stress promotes the aggregation of disease proteins, and contributes to age- and disease-related proteostatic collapse [41, 42].…”

Mitochondria and aging: A role for the mitochondrial transition pore?

“…mPTP opening also plays a role in the neuronal injury relevant to neurodegenerative diseases increasing in aging populations such as Alzheimer's, Parkinson's, and amyloid lateral sclerosis diseases ( Angelova & Abramov, 2017; Du et al., 2008; Gandhi et al., 2009; Martin et al., 2009 ). This is particularly true for Alzheimer's disease which is characterized by the presence of extracellular senile plaques, mainly composed of amyloid‐β (Aβ) peptide and intracellular neurofibrillary tangles made up of hyperphosphorylated tau protein (Selkoe, 2004).…”

Insights into the Mechanisms Involved in Protective Effects of VEGF-B in Dopaminergic Neurons

“…The first gene to be linked to familial PD was SNCA , which encodes the protein α -synuclein, and since α -synuclein is also a main contributor to Lewy bodies in idiopathic PD it is of special importance for PD. Both monomeric and oligomeric forms of α -synuclein have differential effects on mitochondria, including increasing calcium, inhibitory effects on complex I activity, and inducing reactive oxygen species (ROS), as reviewed in [9]. Another familial form of early-onset PD can be caused by mutations in PTEN-induced kinase 1 (PINK1), where PINK1 mutations or knockdown of PINK1 results in an increase of α -synuclein aggregates in cell-culture PD models, decrease in mitochondrial respiration, and a decrease in ATP synthesis [3].…”