Recent Advances in Autophagy and Immunotherapy for the Clearance of Aggregated α-Synuclein in Parkinson's Disease.

Parkinson's disease is a neurodegenerative condition characterized by the accumulation of misfolded and aggregated α-synuclein in Lewy bodies and neurites. These protein aggregates contribute to neurodegeneration and motor symptoms such as bradykinesia, rigidity, and tremor. While the ubiquitin-proteasome system degrades soluble α-synuclein, aggregated and oligomeric forms are primarily cleared via the autophagy-lysosomal pathway. Mutations of the SNCA gene exacerbate α-synuclein aggregation and significantly impair its clearance, highlighting the importance of targeting toxic α-synuclein species. Strategies such as promoting autophagosome formation via 5'-AMP-activated protein kinase (AMPK) and mechanistic target of rapamycin complex 1 (mTORC1) or facilitating autophagosome maturation via RAB7-a member of the RAS oncogene family-and related effectors, have shown promise in enhancing autophagy and reducing α-synuclein pathology. Pharmacological agents such as rapamycin, trehalose, and nilotinib have demonstrated preclinical efficacy in enhancing α-synuclein clearance and alleviating disease features. Concurrently, immunotherapy approaches, including passive and active immunization, aim to enhance the immune system's ability to recognize and eliminate toxic α-synuclein species. Emerging strategies such as peptide-based therapies aim to inhibit aggregation or promote degradation of α-synuclein. At the same time, nanotechnology enables the targeted delivery of therapeutic agents across the blood-brain barrier with improved efficiency. Additionally, novel AUTOTAC (autophagy-targeting chimera) platforms offer a precision strategy to tag α-synuclein for autophagic degradation. This review explores many advances in autophagy-mediated aggregated α-synuclein clearance, emphasizing its potential as a therapeutic strategy to address the limitations of current symptomatic treatments and slow the progression of Parkinson's disease.