Editors' ChoiceParkinson’s Disease

Nosing around α-synuclein

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Science Translational Medicine  28 Aug 2019:
Vol. 11, Issue 507, eaaz0303
DOI: 10.1126/scitranslmed.aaz0303

Abstract

Neurons from the olfactory mucosa in combination with a highly sensitive amplification assay may offer a monitoring paradigm for α-synucleinopathies.

Parkinson’s disease (PD) and multiple system atrophy (MSA) are members of the family of α-synucleinopathies. These diseases are characterized by the accumulation of abnormally folded α-synuclein protein (α-SYN) in the central nervous system. Early diagnosis is imperative for optimal disease management. However, the clinical features of PD and MSA can often overlap with other neurodegenerative diseases, caused by other misfolded proteins, making diagnosis challenging. Assaying α-SYN aggregation in neurons is a potential way to increase diagnostic specificity.

Typically, only invasive biopsy allows access to neurons to determine the presence of disease-associated protein. However, sensory neurons within the olfactory mucosa (OM) are accessible through the nasal canal and can be collected with careful swabbing of this area. De Luca et al. utilize this nasal swabbing in combination with an ultra-sensitive assay for detecting disease-associated α-SYN. The real-time quaking-induced conversion (RT-QuIC) assay uses the propensity of abnormally folded proteins to seed conversion of a naïve substrate, in this case α-SYN, which amplifies the abnormally folded forms and allows their detection. The authors show that α-SYN seeds within the OM could be detected in 56% and 82% of patients with PD and MSA, respectively. The reaction was not highly specific, showing positivity in 16% of patients with diseases caused by accumulation of a TAU protein, such as corticobasal degeneration and progressive supranuclear palsy. A possible explanation for the lower than ideal sensitivity and specificity lies in using living patients with a probable rather than autopsy-confirmed diagnosis. Despite this, the authors did find that the fibrils produced by amplification of α-SYN in the RT-QuIC reaction varied depending upon the disease seed, therefore supporting the hypothesis that different “strains” of α-SYN could impart their conformations onto the same substrate.

Analytical use of OM is exciting as swabs are minimally invasive and can be taken repeatedly throughout the course of disease and treatment. Unfortunately, it seems unlikely that this assay represents a viable diagnostic test in its current form, and the authors acknowledge that additional studies are needed. Nonetheless, the potential to monitor disease course and therapeutic efficacy could provide immensely valuable information on the disease progression within neurons.

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