Mitochondrial Dysfunction, Protein Misfolding and Neuroinflammation in Parkinson’s Disease: Roads to Biomarker Discovery

Abstract

Parkinson’s Disease (PD) is a highly prevalent neurodegenerative disease among older adults. PD neuropathology is marked by the progressive loss of the dopaminergic neurons of the substantia nigra pars compacta and the widespread accumulation of misfolded intracellular α-synuclein (α-syn). Genetic mutations and post-translational modifications, such as α-syn phosphorylation, have been identified among the multiple factors supporting α-syn accrual during PD. A decline in the clearance capacity of the ubiquitin-proteasome and the autophagy-lysosomal systems, together with mitochondrial dysfunction, have been indicated as major pathophysiological mechanisms of PD neurodegeneration. The accrual of misfolded α-syn aggregates into soluble oligomers, and the generation of insoluble fibrils composing the core of intraneuronal Lewy bodies and Lewy neurites observed during PD neurodegeneration, are ignited by the overproduction of reactive oxygen species (ROS). The ROS activate the α-syn aggregation cascade and, together with the Lewy bodies, promote neurodegeneration. However, the molecular pathways underlying the dynamic evolution of PD remain undeciphered. These gaps in knowledge, together with the clinical heterogeneity of PD, have hampered the identification of the biomarkers that may be used to assist in diagnosis, treatment monitoring, and prognostication. Herein, we illustrate the main pathways involved in PD pathogenesis and discuss their possible exploitation for biomarker discovery.

Therapeutic application of quercetin in aging-related diseases: SIRT1 as a potential mechanism

“…Oxidative stress is a major inducers of PD pathogenesis. This is because ROS activates a-syn aggregation cascade, together with Lewy bodies, promotes neurodegeneration (69). In a 6hydroxydopamine (6-OHDA) PD rat model, it was observed that quercetin alleviated the unilateral medial forebrain tract (annigra lesion) or the striatum (part lesion) through the antioxidant, anti-inflammatory, and protective neurotransmitter mechanisms (70)(71)(72).…”

Baicalein Induces Mitochondrial Autophagy to Prevent Parkinson's Disease in Rats via miR-30b and the SIRT1/AMPK/mTOR Pathway

“…The pathogenesis of PD is closely associated with mitochondrial dysfunction ( 9 , 32 ). The mitochondrial ultrastructure of neurons in substantia nigra of rats was observed using a TEM.…”

Gene therapy of yeast NDI1 on mitochondrial complex I dysfunction in rotenone-induced Parkinson’s disease models in vitro and vivo

“…Besides the reduced complex I activity, the increased mitochondria-derived reactive oxygen species (ROS) production, has been implicated in the pathogenesis of PD (Choong and Mochizuki 2017 ; Picca et al 2021 ). In order to explore the level of oxidative stress after NDI1 transduction to rotenone-induced cell model, MitoSOX™, a specific dye that can recognize mitochondrial superoxide anion free radicals, was used to examine the level of ROS in mitochondria.…”