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α-Synuclein Seed Amplification Assays for Diagnosing Synucleinopathies: The Way Forward
Giovanni Bellomo1, Chiara Maria Giulia De Luca1, Federico Paolini Paoletti1
1From the Section of Neurology, Lab of Clinical Neurochemistry, Department of Medicine and Surgery, University of Perugia, Italy (G.B., F.P.P., L.G., L.P.); and Unit of Neurology 5 and Neuropathology (C.M.G.D.L., F.M.), Fondazione IRCCS Istituto Neurologico Carlo Besta, Milan, Italy.
Seed amplification assays (SAAs) show promise for early Parkinson disease (PD) diagnosis by detecting misfolded alpha-synuclein (α-syn) in various samples. These assays can differentiate PD and other synucleinopathies even in early stages, paving the way for molecular diagnosis.
Area of Science:
- Neurodegenerative diseases
- Prion-like protein aggregation
- Molecular diagnostics
Background:
- Parkinson disease (PD) is the second most common neurodegenerative disease and the primary synucleinopathy.
- Current PD diagnosis relies on motor symptoms, delaying detection until disease progression.
- Misfolded alpha-synuclein (α-syn) aggregation precedes clinical PD onset, offering a diagnostic window.
Purpose of the Study:
- To review the clinical application of alpha-synuclein (α-syn) Seed Amplification Assays (SAAs) for diagnosing PD and other synucleinopathies.
- To highlight the potential of SAAs in enabling early, molecular diagnosis of PD.
- To discuss current challenges and future directions for SAAs in synucleinopathy diagnosis.
Main Methods:
- Seed Amplification Assays (SAAs) adapted for detecting misfolded α-synuclein.
- Analysis of α-syn detection in various biological samples including CSF, saliva, and biopsies.
- Kinetic analysis of SAA fluorescence profiles to identify α-syn fibril conformations (strains).
Main Results:
- SAAs successfully detect misfolded α-syn in patients with PD and other synucleinopathies across different sample types.
- SAAs differentiate synucleinopathies (PD, dementia with Lewy bodies, multiple system atrophy) from controls and non-synucleinopathy parkinsonisms, even in prodromal stages.
- Kinetic analysis of SAAs can distinguish between different synucleinopathy strains, particularly Lewy body diseases and MSA.
Conclusions:
- α-syn SAAs represent a highly promising diagnostic biomarker for synucleinopathies, enabling early and molecular diagnosis.
- SAAs have the potential to significantly improve the differential diagnosis of parkinsonian disorders.
- Standardization of preanalytical and analytical aspects of SAAs is crucial for widespread clinical adoption.
