Treating Parkinson's Disease with Antibodies: Previous Studies and Future Directions

Abstract

Parkinson's disease is a neurodegenerative disorder mainly characterized by the degeneration of dopaminergic neurons in the substantia nigra. Degenerating neurons contain abnormal aggregates called Lewy bodies, that are predominantly composed of the misfolded and/or mutated alpha-synuclein protein. Post-translational modifications, cellular stress, inflammation and gene mutations are thought to trigger its pathological misfolding and aggregation. With alpha-synuclein pathology being strongly associated with dopaminergic neuronal toxicity, strategies aimed to reduce its burden are expected to be beneficial in slowing disease progression. Moreover, multiple sources of evidence suggest a cell-to-cell transmission of pathological alpha-synuclein in a prion-like manner. Therefore, antibodies targeting extra- or intracellular alpha-synuclein could be efficient in limiting the aggregation and transmission. Several active and passive immunization strategies have been explored to target alpha-synuclein. Here, we summarize immunotherapeutic approaches that were tested in pre-clinical or clinical studies in the last two decades in an attempt to treat Parkinson's disease.

Keywords: Parkinson’s disease; alpha-synuclein; antibodies; immunotherapy; intrabodies.; nanobodies; prion-like.

Fig.1

Principal hallmarks of Parkinson’s disease. Parkinson’s disease is characterized by the loss of dopaminergic neurons in the substantia nigra. Affected neurons present insoluble aggregates in their cytoplasm and neurites called Lewy bodies and Lewy neurites, respectively. These inclusions are predominantly composed of the protein alpha-synuclein. Activated microglia releasing pro-inflammatory cytokines are also present and promote an inflammatory environment possibly contributing to neuronal loss. Dopaminergic neuron degeneration leads to the classical motor symptoms. It is hypothesized that the affection of non-dopaminergic neurons in other brain regions would be responsible for the various non-motor symptoms that also greatly affect quality of life. (Created with BioRender)

Fig.2

Proposed mechanism for the pathological transmission of aSyn and possible immunotherapeutic targets. 1) Post-translational modifications, cellular stress and mutations can trigger the misfolding and aggregation of aSyn into oligomers and fibrils. 2) Toxic forms of aSyn can be released in the extracellular space by unconventional exocytosis. 3) Once in the extracellular space, aggregated aSyn can be internalized by neighboring cells by endocytosis through binding of specific receptors. 4) Misfolded aSyn can act as a nucleating seed to trigger the misfolding of the endogenous protein. This process, called “permissive templating”, is thought to occur inside endosomes and lysosomes. 5) Monoclonal antibodies with different strain specificity can bind extracellular aSyn. 6) The immune complex can be internalized by microglia through the FCγRIII and is degraded intracellularly. 7) Unbound monoclonal antibodies can be internalized by neurons through the FCγRI and bind intracellular aSyn. 8) Single-chain variable fragment antibodies or single-domain antibodies (nanobodies) can be delivered as genes with viral vectors. 9) These intrabodies can target intracellular aSyn to prevent aggregation and can be engineered to be more efficient in stimulating degradation. 10) Antibodies can also target cell surface receptors used by aSyn to enter the cells (e.g., LAG3) to prevent entry. (Created with BioRender.com)