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.

Keywords: amyloid beta; mitochondrial dysfunction; oxidative stress; proteinopathy; α-synuclein.

Figure 1

Amyloid beta proteinopathy in AD brain. Notes: Oxidative stress causes increased expression of APP and BACE1, leading to accumulation of Aβ42. The clearance of Aβ42 from the brain is also retarded by oxidative stress. On the other hand, the multiple interactions of Aβ42 with mitochondria, microglia and metal ions lead to further oxidative stress. Arrows suggest interactions; a line with an end bar indicates retardation. Abbreviations: Aβ42, amyloid beta peptide 1–42; AD, Alzheimer’s disease; APP, amyloid precursor protein; BACE1, β-secretase; eIF2, eukaryotic initiation factor-2; IRE, iron-responsive element; LRP1, low-density lipoprotein receptor-related protein 1; PKR, double-stranded RNA-dependent protein kinase; RAGE, receptor for advanced glycation end products; ROS, reactive oxygen species.

Figure 2

Pathways of α-synuclein accumulation and toxicity in PD. Notes: The accumulation of excess α-synuclein occurs in the PD brain through diminished degradation, increased transcription of SNCA and iron/IRE-regulated posttranscriptional mechanisms. Alpha-synuclein (monomers and oligomers) have multiple interactions with mitochondria, causing dysfunction of the organelle and increasing ROS production. Iron and DA-oxidation products contribute to oxidative stress in the PD brain, which is further enhanced by iron–α-synuclein interactions. The arrows indicate interactions, but arrows with end bars suggest inhibition. Abbreviations: DA, dopamine; IRE, iron-responsive element; PD, Parkinson’s disease; ROS, reactive oxygen species; SNCA, α-synuclein gene.