Aggregation and beyond: alpha-synuclein-based biomarkers in synucleinopathies

Parkinson's disease is clinically known for the loss of dopaminergic neurons in the substantia nigra pars compacta and accumulation of intraneuronal cytoplasmic inclusions rich in alpha-synuclein called 'Lewy bodies' and 'Lewy neurites'. Together with dementia with Lewy bodies and multiple system atrophy, Parkinson's disease is part of a group of disorders called synucleinopathies. Currently, diagnosis of synucleinopathies is based on the clinical assessment which often takes place in advanced disease stages. While the causal role of alpha-synuclein aggregates in these disorders is still debatable, measuring the levels, types or seeding properties of different alpha-synuclein species hold great promise as biomarkers. Recent studies indicate significant differences in peptide, protein and RNA levels in blood samples from patients with Parkinson's disease. Seed amplification assays using CSF, blood, skin biopsy, olfactory swab samples show great promise for detecting synucleinopathies and even for discriminating between different synucleinopathies. Interestingly, small extracellular vesicles, such as exosomes, display differences in their cargoes in Parkinson's disease patients versus controls. In this update, we focus on alpha-synuclein aggregation and possible sources of disease-related species released in extracellular vesicles, which promise to revolutionize the diagnosis and the monitoring of disease progression.