Abstract
Diagnosis of ALS is based on clinical symptoms when motoneuron degeneration is significant. Therefore, new approaches for early diagnosis are needed. We aimed to assess if alterations in appearance and cellular localization of cutaneous TDP-43 may represent a biomarker for ALS. Skin biopsies from 64 subjects were analyzed: 44 ALS patients, 10 healthy controls (HC) and 10 neurological controls (NC) (Parkinson’s disease and multiple sclerosis). TDP-43 immunoreactivity in epidermis and dermis was analyzed, as well as the percentage of cells with TDP-43 cytoplasmic localization. We detected a higher amount of TDP-43 in epidermis (p < 0.001) and in both layers of dermis (p < 0.001), as well as a higher percentage of TDP-43 cytoplasmic positive cells (p < 0.001) in the ALS group compared to HC and NC groups. Dermal cells containing TDP-43 were fibroblasts as identified by co-labeling against vimentin. ROC analyses (AUC 0.867, p < 0.001; CI 95% 0.800–0.935) showed that detection of 24.1% cells with cytoplasmic TDP-43 positivity in the dermis had 85% sensitivity and 80% specificity for detecting ALS. We have identified significantly increased TDP-43 levels in epidermis and in the cytoplasm of dermal cells of ALS patients. Our findings provide support for the use of TDP-43 in skin biopsies as a potential biomarker.
Highlights
Amyotrophic lateral sclerosis (ALS) is a neurodegenerative disorder affecting motor neurons from cortex, brainstem, and spinal cord
TAR DNA-binding protein (TDP-43) is a ubiquitous DNA binding protein with multiple functions encoded by the TARDBP gene, and its mutations have been associated with autosomal dominant ALS and frontotemporal dementia (FTD) [7,8]
Our results show an increase in TDP-43 in ALS patients in both epidermis and dermis, establishing a proof-of-concept of its possible value in the diagnosis of this pathology
Summary
Amyotrophic lateral sclerosis (ALS) is a neurodegenerative disorder affecting motor neurons from cortex, brainstem, and spinal cord. The importance of TDP-43 in ALS relies on the fact that it is a major component of the ubiquitinated insoluble cytoplasmic inclusions, concomitant with a loss of nuclear TDP-43 in upper and lower motor neurons and in other regions of the central nervous system in most patients (both sporadic and familial, with or without TARDBP mutations) [10]. These inclusions are widespread, regardless of the location of symptoms onset, and considered a pathological hallmark of ALS-FTD spectrum [11,12]. The TDP-43 protein is located in the nucleus, suggesting that the increased
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