Molecular and Cellular Interactions in Pathogenesis of Sporadic Parkinson Disease

Abstract

An increasing number of the population all around the world suffer from age-associated neurodegenerative diseases including Parkinson’s disease (PD). This disorder presents different signs of genetic, epigenetic and environmental origin, and molecular, cellular and intracellular dysfunction. At the molecular level, α-synuclein (αSyn) was identified as the principal molecule constituting the Lewy bodies (LB). The gut microbiota participates in the pathogenesis of PD and may contribute to the loss of dopaminergic neurons through mitochondrial dysfunction. The most important pathogenetic link is an imbalance of Ca2+ ions, which is associated with redox imbalance in the cells and increased generation of reactive oxygen species (ROS). In this review, genetic, epigenetic and environmental factors that cause these disorders and their cause-and-effect relationships are considered. As a constituent of environmental factors, the example of organophosphates (OPs) is also reviewed. The role of endothelial damage in the pathogenesis of PD is discussed, and a ‘triple hit hypothesis’ is proposed as a modification of Braak’s dual hit one. In the absence of effective therapies for neurodegenerative diseases, more and more evidence is emerging about the positive impact of nutritional structure and healthy lifestyle on the state of blood vessels and the risk of developing these diseases.

Leucine‐rich repeat kinase 2 (LRRK2) inhibition upregulates microtubule‐associated protein 1B to ameliorate lysosomal dysfunction and parkinsonism

“…As previously reported, 35–37 sporadic PD accounts for approximately 85%–95% of all PD cases. It may result from a complex interplay of genetic susceptibility, environmental factors, age‐related changes, oxidative stress, mitochondrial dysfunction, protein misfolding and aggregation, and neuroinflammation 38,39 . Epidemiological studies across diverse populations have consistently demonstrated a relatively higher frequency (1%–2%) of mutations of LRRK 2 in sporadic PD patients 40 .…”

“…It may result from a complex interplay of genetic susceptibility, environmental factors, age-related changes, oxidative stress, mitochondrial dysfunction, protein misfolding and aggregation, and neuroinflammation. 38,39 Epidemiological studies across diverse populations have consistently demonstrated a relatively higher frequency (1%-2%) of mutations of LRRK2 in sporadic PD patients. 40 Furthermore, genetic association studies have revealed an association between specific LRRK2 variants and the risk of sporadic PD.…”

Exploring the Role of ACE2 as a Connecting Link between COVID-19 and Parkinson’s Disease

“…Then, Lewy pathology may spread throughout various brain regions in a stereotypical manner, while it affects dopaminergic neuronal cells in the substantia nigra several years later [ 65 ]. Although the pathogenesis of PD remains elusive, several pathophysiological mechanisms, including oxidative stress, neuroinflammation, mitochondrial dysfunction, abnormal protein aggregation and spreading, autophagy dysregulation, impaired apoptotic mechanisms, and gut microbiome imbalance, are implicated in its development [ 66 , 67 , 68 , 69 ]. Increased levels of tumor necrosis factor alpha (TNF) and interleukin 1β (IL-1-β) have been related to increased PD risk [ 70 ].…”