Methods for detecting toxic α-synuclein species as a biomarker for Parkinson’s disease

Abstract

Parkinson’s disease (PD) is the most common neurodegenerative movement disorder and is characterized by the accumulation of α-synuclein (α-syn) into insoluble aggregates known as Lewy bodies and Lewy neurites in the brain. However, prior to the formation of these large aggregates, α-syn forms oligomers and small fibrils, which are believed to be the pathogenic species leading to the death of neurons in the substantia nigra in disease. The majority of aggregated α-syn is phosphorylated, and it is thought that this post-translational modification may be critical in disease pathogenesis. Thus, early detection of the toxic forms of α-syn may provide a window of opportunity for an intervention to halt or slow the progression of neurodegeneration in PD. Expression of α-syn is not restricted to the central nervous system and the protein can be found elsewhere, including bodily fluids and peripheral tissues. This review will examine current methods for detecting toxic forms of α-syn in accessible biospecimens and outline emerging techniques that may provide reliable identification of biomarkers for PD.

Keywords:

• Neurodegeneration
• protein aggregation
• seed amplification
• proximity ligation assay
• biofluid-based detection

Disclosure statement

No potential conflict of interest was reported by the author(s).

Table 1. Antibodies used for the detection of specific forms of α-syn.

Addendum

Since the review and acceptance of this manuscript, Shahnawaz and colleagues [167] have demonstrated that PMCA can discriminate between CSF and brain samples from patients diagnosed with PD versus those diagnosed with MSA. The plateau of fluorescence after α-syn PMCA was significantly greater in samples from PD patients and demonstrated an overall sensitivity of 95.4%. Their findings support the hypothesis that different strains of α-syn are associated with PD and MSA and highlight our suggestion that investigations into the folding kinetics of α-syn specific to each α-synucleinopathy may yield greater diagnostic potential.

Additional information

Funding

LVK holds a Clinician-Scientist Award from the Canadian Institutes of Health Research. DMO was supported by a Postdoctoral Fellowship Award from the Krembil Research Institute.