Unraveling synucleinopathies: Recent breakthroughs in Parkinson's disease therapy

Parkinson's disease is the most prevalent disorder among a group of conditions known as synucleinopathies. It is characterized by the presence of intracellular inclusions composed of misfolded α-synuclein (α-Syn) protein within neurons of the central and peripheral nervous systems. The antibody-based immunotherapeutic approach has substantial promise in treating various types of synucleinopathies, including Parkinson's disease. This review critically examines the pathomechanistic impact of α-Syn on the cellular environment, with a focus on neuroinflammation and immune responses. Various strategies, including active and passive immunization, have been investigated to counteract synucleinopathies. We provide an overview of antibody-based strategies investigated in human clinical trials for the treatment of Parkinson's disease, focusing on cutting-edge approaches, including vaccination therapy, engineered antibody fragments, intrabodies, and nanobodies, designed to combat neuroinflammation-induced neurodegeneration. Harnessing immunotherapy to modulate immune activation has garnered significant interest as a potential therapeutic avenue for various inflammation-linked neurodegenerative disorders. Multiple strategies, including active and passive immunization, have been investigated to target α-Syn. The intricate process of selecting the most effective anti-α-Syn antibody for treating human synucleinopathies requires careful consideration. Additionally, the need for future research and clinical trials must prioritize unlocking the full potential of the immune system to advance our understanding of synucleinopathies. SIGNIFICANCE STATEMENT: This minireview explores recent advances in α-Syn-targeted immunotherapy, antibody fragments, intrabodies, and nanobodies. It highlights their mechanisms and potential to reshape Parkinson's disease treatment through the development of next-generation immunotherapeutics.