Alpha-synuclein in Parkinson's disease: a villain or tragic hero? A critical view of the formation of α-synuclein aggregates induced by dopamine metabolites and viral infection

ABSTRACT

Introduction

Since the discovery of the presynaptic protein α-synuclein (aSyn) as a central player in Parkinson’s disease (PD), several key questions on the function of the protein in neurodegeneration processes remain unclear, including: is there a synergy between dopamine metabolism and the formation of toxic aSyn species in neurons? What is the role of aSyn in the immunological system?

Areas covered

Herein, the authors revisit the intricate pathways related to dopamine metabolism and how it impacts on aSyn aggregation/function. Additionally, they discuss the importance of aSyn in the immune response to viral infections as well as the current findings on the possible protective role of certain virus vaccines against PD and other neuropathologies.

Expert opinion

The physiological function of aSyn seems to cover different pathways, such as immune response against infections and a neuroprotective role, besides the already-established regulation of synaptic vesicle trafficking. Clinical studies with monoclonal antibodies against aSyn aggregates have shown disappointing results in patients with early-stage PD. Alternatively, we could consider, as immunological target, specific neurotoxic oligomers of aSyn formed in the presence of dopamine metabolites, such as DOPAL. Nevertheless, the crucial question remains as to whether removing these protein deposits will affect the clinical course of the disease.

KEYWORDS:

• Α-synuclein
• DOPAL
• dopamine
• immune system
• oligomers
• Parkinson´s disease
• vaccination
• virus infection

Article highlights

• The formation of Lewy bodies in dopaminergic neurons in PD suggests that factors intrinsically linked to dopamine metabolism may be involved in stabilization of potentially toxic forms of the protein.

• DOPAL occupies a central role in the toxic events that lead to the degeneration of dopaminergic neurons.

• Alpha-syn plays an important role in reducing apoptosis induced by certain oxidative stressors.

• An increase of expression of aSyn is important for the recruitment of immune cells in which the protein participates of the activation of immune responses against pathogens.

• Macaques infected with SARS-CoV-2 exhibit CNS inflammation accompanied by the formation Lewy bodies in the brain.

Declaration of interest

The authors have no other relevant affiliations or financial involvement with any organization or entity with a financial interest in or financial conflict with the subject matter or materials discussed in the manuscript apart from those disclosed.

Reviewer disclosures

Peer reviewers on this manuscript have no relevant financial or other relationships to disclose.

Additional information

Funding

This work was supported by the Carlos Chagas Foundation for Research Support of the State of Rio de Janeiro (FAPERJ) (E-26/202.657/2019; E-26/010.002259/2019; SEI- 260003/001131/2020; E-26/211.368/2021) and the Brazilian National Council for Scientific and Technological Development (CNPq) for a Research Productivity Fellowship (to C Follmer)