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

Abnormal accumulation of microtubule-associated protein tau (tau) is a characteristic feature of atypical parkinsonisms with tauopathies, such as progressive supranuclear palsy and corticobasal degeneration. However, pathological tau has also been observed in alpha-synucleinopathies like Parkinson's disease and multiple system atrophy. Based on the involvement of the peripheral nervous system in several neurodegenerative diseases, we characterized and compared tau expression in skin biopsies of patients clinically diagnosed with Parkinson's disease, multiple system atrophy, progressive supranuclear palsy and corticobasal degeneration and in healthy control subjects. In all groups, tau protein was detected along both somatosensory and autonomic nerve fibres 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 were more expressed in progressive supranuclear palsy/corticobasal degeneration by real-time PCR. Enzyme-linked immunosorbent assay demonstrated significantly higher levels of total tau protein in skin lysates of progressive supranuclear palsy/corticobasal degeneration compared to the other groups. Multivariate regression analysis and receiver operating characteristics curve analysis of tau amount at both sites showed a clinical association with tauopathies diagnosis and high diagnostic value for progressive supranuclear palsy/corticobasal degeneration versus Parkinson's disease (sensitivity 90%, specificity 69%) and progressive supranuclear palsy/corticobasal degeneration versus multiple system atrophy (sensitivity 90%, specificity 86%). tau protein increase correlated with cognitive impairment in progressive supranuclear palsy/corticobasal degeneration. This study is a comprehensive characterization of tau in the human cutaneous peripheral nervous system in physiologic and pathologic conditions. The differential expression of tau, 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. Vacchi et al. compare tau expression in skin biopsies from patients clinically diagnosed with Parkinson's disease, MSA, PSP and CBD, and healthy controls. The differential expression of tau, both at transcript and protein levels, suggests that skin biopsy can help in discriminating between neurodegenerative diseases.