Alpha-Synuclein Biomarkers in Neurodegenerative Disorders

Alpha-synuclein is a neuronal protein whose misfolding and aggregation underlie a group of disorders termed synucleinopathies, chief among them Parkinson’s disease (PD), dementia with Lewy bodies (DLB) and multiple system atrophy (MSA). Peripheral and fluid biomarkers have emerged as vital tools to detect pathological alpha-synuclein species non-invasively and at prodromal stages. Approaches include immunofluorescence of skin and mucosal biopsies, seed amplification assays in cerebrospinal fluid (CSF) and plasma, and quantification of oligomeric or phosphorylated forms in saliva or blood. These methods vary in sensitivity, specificity and quantitative capacity, but when combined they promise early diagnosis, stratification of clinical variants, monitoring of disease progression and optimisation of clinical trial enrolment. Global efforts focus on standardising collection sites, assay protocols and interpretative thresholds to translate these biomarkers into routine practice.

Research from Nature Portfolio

In a foundational in vivo study, researchers compared alpha-synuclein deposition across clinical variants by analysing skin biopsies from patients with idiopathic PD, DLB, pure autonomic failure and MSA alongside healthy controls. Phosphorylated alpha-synuclein proved the most sensitive and specific marker. Distinct patterns emerged: autonomic fibre deposits predominated in PD, DLB and pure autonomic failure at proximal sites, whereas MSA showed somatic fibre involvement chiefly at distal sites. Quantitative differences in load and localisation aligned with clinical phenotype, supporting the use of skin p-syn profiling for differential diagnosis and insight into disease mechanisms.

Alpha-Synuclein Biomarkers in Neurodegenerative Disorders publication trend

The graph below shows the total number of articles in alpha-synuclein biomarkers in neurodegenerative disorders across all publications each year (not limited to Nature Index journals).

Technical terms

Alpha-synuclein: A presynaptic neuronal protein that aggregates into Lewy bodies and Lewy neurites in synucleinopathies.
Biomarker: A biological molecule or measure that indicates normal or pathological processes or responses to therapy.
Seed amplification assay: A sensitive method exploiting prion-like propagation of misfolded proteins to detect minute pathological species.
Immunofluorescence: A technique using fluorescently labelled antibodies to visualise specific proteins within tissue sections.
Oligomeric alpha-synuclein: Small, soluble aggregates of alpha-synuclein considered toxic and indicative of early pathology.
Phosphorylated alpha-synuclein: Alpha-synuclein modified at serine 129, commonly enriched in disease-associated aggregates.

References

1. A comparative blind study between skin biopsy and seed amplification assay to disclose pathological α-synuclein in RBD. npj Parkinson's Disease (2023).
2. Fluid and Biopsy Based Biomarkers in Parkinson's Disease. Neurotherapeutics (2023).
3. Evaluating the Diagnostic Potential of Combined Salivary and Skin Biomarkers in Parkinson’s Disease. International Journal of Molecular Sciences (2024).
4. Skin α-synuclein deposits differ in clinical variants of synucleinopathy: an in vivo study. Scientific Reports (2018).