Tau protein quantification in skin biopsies differentiates tauopathies from alpha-synucleinopathies

Brain. 2022 Apr 29;awac161. doi: 10.1093/brain/awac161. Online ahead of print.

Abstract

Abnormal accumulation of microtubule-associated protein tau (τ) is a characteristic feature of atypical parkinsonisms with tauopathies such as Progressive Supranuclear Palsy (PSP) and Corticobasal Degeneration (CBD). However, pathological τ has also been observed in α-synucleinopathies like Parkinson's Disease (PD) and Multiple System Atrophy (MSA). Based on the involvement of peripheral nervous system in several neurodegenerative diseases, we characterized and compared τ expression in skin biopsies of patients clinically diagnosed with PD, MSA, PSP, CBD, and in healthy control subjects. In all groups, τ protein was detected along both somatosensory and autonomic nerve fibers in the epidermis and dermis by immunofluorescence. We found by western blot the presence of mainly two different bands at 55 and 70 KDa, co-migrating with 0N4R/1N3R and 2N4R isoforms, respectively. At the RNA level, the main transcript variants were 2N and 4R, and both resulted more expressed in PSP/CBD by real-time PCR. ELISA assay demonstrated significantly higher levels of total τ protein in skin lysates of PSP/CBD compared to the other groups. Multivariate regression analysis and ROC curves analysis of τ amount at both sites showed a clinical association with tauopathies diagnosis and high diagnostic value for PSP/CBD vs. PD (sensitivity 90%, specificity 69%) and PSP/CBD vs. MSA (sensitivity 90%, specificity 86%). τ protein increase correlated with cognitive impairment in PSP/CBD. This study is a comprehensive characterization of τ in the human cutaneous peripheral nervous system in physiologic and pathologic conditions. The differential expression of τ, both at transcript and protein levels, suggests that skin biopsy, an easily accessible and minimally invasive exam, can help in discriminating among different neurodegenerative diseases.

Keywords: Parkinson’s disease; biomarkers; skin biopsy; tau protein; tauopathies.