Alpha-Synuclein in Parkinson’s

Home page Description: 
Ground-breaking therapies that tackle alpha-synuclein in Parkinson’s disease.
Posted On: October 20, 2017
Image Caption: 
Conference attendee and graduate student Krystal Menezes (pictured) works in the laboratory of Dr. Lorraine Kalia.

Conference Details: “20 years of alpha-synuclein in Parkinson's disease and related synucleinopathies: from the bedside to the bench and back to the patient.” September 7-10, 2017, Athens, Greece

Conference Highlight: A promising avenue for combating alpha-synuclein toxicity involves complementing alpha-synuclein reduction therapies with therapies that target alpha-synuclein-induced inflammation and pathological immune responses.

Conference Summary: The conference shed light on new and emerging disease-modifying therapies.

An interesting talk, related to our work at Krembil, focused on the use of small molecules to combat alpha-synuclein and its associated neuropathology. Because the endogenous function of alpha-synuclein is not well understood and it exists as a free unfolded protein, small molecules must be chosen that target a specific conformer of alpha-synuclein. Without taking this precaution, new therapeutics would be more likely to cause unwanted side effects.

A relatively new emerging area of interest in the alpha-synuclein field is the interaction between alpha-synuclein and the immune system. The microbiota and peripheral immune response shape the immune reactions to alpha-synuclein. CD163+ cells MHCII cells play a key role in neurotoxicity and inflammation. CD163 is a hemoglobin scavenger receptor expressed in monocyte macrophages that has been found in macrophages that reside in the wall of the GI tract or the brain. Results presented at the conference revealed that depleting CD163+ cells led to reduced cell death. Thus, targeting CD163+ cells along with alpha-synuclein could be a promising therapeutic strategy.

Alpha-synuclein also affects the immune system through its interaction with toll-like receptor 2 (TLR2). Alpha-synuclein triggers an innate immune response via TLR2 and induces the paracrine activation of microglia. Antibody neutralization of TLR2 was shown to reduce alpha-synuclein-induced toxicity and inflammation.

Lastly, using a glucan particle vaccine delivery system that specifically targets antigen-presenting cells, researchers delivered both rapamycin and an alpha-synuclein-antibody to LC3-GFP macrophage cell lines. This treatment works by reducing inflammatory factors such as IL-6 and TNFɑ to inhibit neurotoxicity, while also simultaneously reducing levels of alpha-synuclein to promote neuroprotection.

Altogether, promising therapeutic strategies for combating alpha-synuclein toxicity involve combining anti-inflammatory drugs with passive immunization against alpha-synuclein.