Targeting Alpha-Synuclein as a Therapy for Parkinson's Disease

Abstract

Parkinson's disease (PD) is one of the most common neurodegenerative disorders with a global burden of approximately 6.1 million patients. Alpha-synuclein has been linked to both the sporadic and familial forms of the disease. Moreover, alpha-synuclein is present in Lewy-bodies, the neuropathological hallmark of PD, and the protein and its aggregation have been widely linked to neurotoxic pathways that ultimately lead to neurodegeneration. Such pathways include autophagy/lysosomal dysregulation, synaptic dysfunction, mitochondrial disruption, and endoplasmic reticulum (ER) and oxidative stress. Alpha-synuclein has not only been shown to alter cellular pathways but also to spread between cells, causing aggregation in host cells. Therapeutic approaches will need to address several, if not all, of these angles of alpha-synuclein toxicity. Here we review the current advances in therapeutic efforts for PD that aim to produce a disease-modifying therapy by targeting the spread, production, aggregation, and degradation of alpha-synuclein. These include: receptor blocking strategies whereby putative alpha-synuclein receptors could be blocked inhibiting alpha-synuclein spread, an alpha-synuclein reduction which will decrease the amount alpha-synuclein available for aggregation and pathway disruption, the use of small molecules in order to target alpha-synuclein aggregation, immunotherapy and the increase of alpha-synuclein degradation by increasing autophagy/lysosomal flux. The research discussed here may lead to a disease-modifying therapy that tackles disease onset and progression in the future.

Keywords: Parkinson’s disease; aggregation; alpha-synuclein; fibrils; oligomers; therapy.

Figure 1

Implicated pathways for α-syn toxicity. To the left, healthy cellular pathways are illustrated, while to the right examples of how these pathways are perturbed in Parkinson’s disease (PD) are shown. Under normal circumstances, autophagic and lysosomal clearance degrades protein and other debris in the cell. In PD these pathways are blocked causing an accumulation of aggregated protein that could itself lead to more aggregation. In healthy cells, endoplasmic reticulum (ER) function is preserved, but in PD ER stress leads to calcium efflux into the cytoplasm. While in healthy cells mitochondrial function and oxidative balance are maintained, in PD the electron transport chain (ETC) and mitochondria function are compromised which causes an increase in reactive oxygen species (ROS) that leads to oxidative stress. Finally, in PD α-syn may interact with synaptobrevin-2, leading to synaptic dysfunction.

Figure 2

Therapeutic strategies for PD. Boosting autophagic/lysosomal clearance is a potential avenue for clearing α-syn and other aggregating proteins that disrupt cellular homeostasis. Reducing SNCA mRNA by modulating histone deacetylase (HDACs) or through RNA interference (RNAi) strategies can potentially lead to a decrease in expression of α-syn which is known to result in reduced aggregation and toxicity. Reducing aggregation can be achieved by impeding the multimerization of α-syn through heat shock proteins (HSPs) for example, or by dissociating existing aggregates with small molecules. Blocking α-syn entry through receptor blocking would directly target the spread of α-syn and prevent its transport from cell to cell. Finally, immunotherapy could potentially neutralize α-syn and/or α-syn aggregates extracellularly and perhaps even intracellularly in the case of intra/nanobodies.