Clinical application of prion-like seeding in alpha-synucleinopathies: Early and non-invasive diagnosis and therapeutic development

The accumulation and deposition of misfolded alpha-synuclein (alpha-Syn) aggregates in the brain is the central event in the pathogenesis of alpha-synucleinopathies, including Parkinson's disease, dementia with Lewy bodies, and multiple-system atrophy. Currently, the diagnosis of these diseases mainly relies on the recognition of advanced clinical manifestations. Differential diagnosis among the various alpha-synucleinopathies subtypes remains challenging. Misfolded alpha-Syn can template its native counterpart into the same misfolded one within or between cells, behaving as a prion-like seeding. Protein-misfolding cyclic amplification and real-time quaking-induced conversion are ultrasensitive protein amplification assays initially used for the detection of prion diseases. Both assays showed high sensitivity and specificity in detection of alpha-synucleinopathies even in the pre-clinical stage recently. Herein, we collectively reviewed the prion-like properties of alpha-Syn and critically assessed the detection techniques of alpha-Syn-seeding activity. The progress of test tissues, which tend to be less invasive, is presented, particularly nasal swab, which is now widely known owing to the global fight against coronavirus disease 2019. We highlight the clinical application of alpha-Syn seeding in early and non-invasive diagnosis. Moreover, some promising therapeutic perspectives and clinical trials targeting alpha-Syn-seeding mechanisms are presented.