Abstract
Parkin and α-synuclein are two key proteins involved in the pathophysiology of Parkinson’s disease (PD). Neurotoxic alterations of α-synuclein that lead to the formation of toxic oligomers and fibrils contribute to PD through synaptic dysfunction, mitochondrial impairment, defective endoplasmic reticulum and Golgi function, and nuclear dysfunction. In half of the cases, the recessively inherited early-onset PD is caused by loss of function mutations in the PARK2 gene that encodes the E3-ubiquitin ligase, parkin. Parkin is involved in the clearance of misfolded and aggregated proteins by the ubiquitin-proteasome system and regulates mitophagy and mitochondrial biogenesis. PARK2-related PD is generally thought not to be associated with Lewy body formation although it is a neuropathological hallmark of PD. In this review article, we provide an overview of post-mortem neuropathological examinations of PARK2 patients and present the current knowledge of a functional interaction between parkin and α-synuclein in the regulation of protein aggregates including Lewy bodies. Furthermore, we describe prevailing hypotheses about the formation of intracellular micro-aggregates (synuclein inclusions) that might be more likely than Lewy bodies to occur in PARK2-related PD. This information may inform future studies aiming to unveil primary signaling processes involved in PD and related neurodegenerative disorders.
Highlights
Published: 31 January 2021Parkinson’s disease (PD) is the second most common neurodegenerative disorder and the most prevalent neurodegenerative movement disorder
As the clinical-pathological expression of PD symptoms does not seem to be dependent on Lewy body formation [164], it has been proposed that the presence of Lewy bodies might be an epiphenomenon rather than a primary event in the PARK2-related PD
Since normally functioning parkin seems to be required for the development of Lewy body pathology, it has been postulated that the parkin-mediated inclusion formation is a neuroprotective effect to circumvent α-synuclein release to the extracellular space and to prevent the spreading of pSer129 α-synuclein fibrils to interconnected neurons [58,59,172,173,174,175]
Summary
Parkinson’s disease (PD) is the second most common neurodegenerative disorder and the most prevalent neurodegenerative movement disorder. These findings highlight the different molecular mechanisms that lead to release of αsynuclein oligomers and fibrils to the extracellular space and their uptake by interconnected neurons This was verified in studies demonstrating that the introduction of exogenous α-synuclein fibrils results in the seeding and recruitment of soluble endogenous α-synuclein leading to the formation of Lewy bodies in human cell lines [58] and mouse hippocampal neurons [59]. The increased cytosolic calcium concentration can be explained by studies demonstrating the ability of α-synuclein oligomers to permeabilize lipid bilayers by creating pore-like structures that cause structural alterations in both the intracellular and plasma membrane This will result in calcium flux from the extracellular space and intracellular stores to the cytosol, thereby activating the CaM-calcineurin cascade leading to toxic effects [75,76]. The precise sequence of intracellular mechanisms of α-synuclein-mediated neurotoxicity that lead to neuronal death in PD remains inconclusive,
Sign-in/Register to view highlights & summary Sign-in/Register to access full text options 
Free) 
Talk to us
Join us for a 30 min session where you can share your feedback and ask us any queries you have
Schedule a call
