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.

Keywords: DAMPs; alpha-synuclein; beta-amyloid (Aβ); cytokine; extracellular vesicles; inflammation; mitochondrial-derived vesicles; mitophagy; neurofilaments light chain (NfL); p-tau pathology.

Figure 1

Schematic representation of the contribution of defective mitochondrial quality control and mitochondrial dysfunction to neurodegeneration in Parkinson’s disease. Mitochondrial dysfunction arising from defective quality control pathways (e.g., mitophagy) ignites the production of reactive oxygen species (ROS) and activates the α-synuclein aggregation cascade. Before reaching its pathological conformation, α-synuclein can be degraded along the endosomal pathway, packaged within multivesicular bodies (MVBs), and released as extracellular vesicles (EVs). In the setting of overwhelmed ubiquitin-proteasome and autophagy-lysosomal systems, misfolded α-synuclein is not efficiently cleared and aggregates into soluble oligomers. These structures generate insoluble fibrils that compose the core of intraneuronal Lewy bodies and Lewy neurites, thereby promoting neurodegeneration. The accrual of misfolded α-synuclein activates microglial cells that attract cells of peripheral immunity within the central nervous system via cytokine release. This instigates a vicious circle resulting in persistent microglial activation which amplifies mitochondrial dysfunction and induces further neuronal damage. Created with BioRender.com, accessed on 9 October 2021.

Figure 2

Schematic representation of the events linking peripheral and neuronal inflammation in Parkinson’s disease. The release of damage-associated molecular patterns (DAMPs) from damaged neurons, including mitochondrial DNA, can be sensed by the microglia which, in coordination with systemic inflammation, recruits inflammatory mediators to fight local impairments and triggers the release of a set of inflammatory mediators to install a pro-inflammatory phenotype in the long term. Microglia activation perpetuates a vicious circle for cytokine release, thereby installing a neuroinflammatory milieu. Created with BioRender.com, accessed on 27 September 2021.