3fb06cdaaf9497f86309a210a4560e47 pmc_35053327.pdf 3ff57e4ea35bbc0a5eb8ef057e7a9ac007ce85eb pmc_35053327.pdf 7ed811ab73423f4593ede6d6adb960e04eb1886ca6d3a62bdc809203278cf974 pmc_35053327.pdf Title: TDP-43 Cytoplasmic Translocation in the Skin Fibroblasts of ALS Patients Subject: 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. Keywords: amyotrophic lateral sclerosis; dermis; skin biopsy; TDP-43; biomarker Author: Miguel A. Rubio, Mireia Herrando-Grabulosa, Roser Velasco, Israel Blasco, Monica Povedano and Xavier Navarro Creator: LaTeX with hyperref Producer: pdfTeX-1.40.21 CreationDate: Tue Jan 11 13:34:46 2022 CET ModDate: Tue Jan 11 13:40:11 2022 CET Tagged: no UserProperties: no Suspects: no Form: none JavaScript: no Pages: 12 Encrypted: no Page size: 595.276 x 841.89 pts (A4) Page rot: 0 File size: 1984137 bytes Optimized: no PDF version: 1.7 name type encoding emb sub uni object ID ------------------------------------ ----------------- ---------------- --- --- --- --------- YFHUPG+VnURWPalladioL Type 1 Custom yes yes no 10 0 IXOQHQ+URWPalladioL-Bold Type 1 Custom yes yes no 15 0 RJCIWW+URWPalladioL-Roma Type 1 Custom yes yes no 20 0 ASAKJA+URWPalladioL-Ital Type 1 Custom yes yes no 24 0 MCBCCI+SourceSansRoman-Regular Type 1C Custom yes yes no 32 0 MCBCCM+SourceSansRoman.613wght Type 1C Custom yes yes no 36 0 MCBCCO+SourceSansRoman-Bold Type 1C Custom yes yes no 40 0 PFKOHU+TimesNewRomanPS-BoldItalicMT Type 1C WinAnsi yes yes no 52 0 QMDDXF+CMSY10 Type 1 Builtin yes yes no 74 0 ZXDKIP+EURM10 Type 1 Builtin yes yes no 78 0 BCDEEE+PalatinoLinotype-Bold TrueType WinAnsi yes yes no 90 0 BCDFEE+PalatinoLinotype-Roman TrueType WinAnsi yes yes no 94 0 BCDGEE+PalatinoLinotype-Italic TrueType WinAnsi yes yes no 98 0 BCDHEE+PalatinoLinotype-Roman CID TrueType Identity-H yes yes yes 102 0 WBVKDJ+URWPalladioL-BoldItal Type 1 Custom yes yes no 117 0 BCDEEE+PalatinoLinotype-Bold TrueType WinAnsi yes yes no 125 0 BCDFEE+PalatinoLinotype-Roman TrueType WinAnsi yes yes no 129 0 BCDGEE+PalatinoLinotype-Italic TrueType WinAnsi yes yes no 133 0 BCDHEE+PalatinoLinotype-Roman CID TrueType Identity-H yes yes yes 137 0 BCDJEE+PalatinoLinotype-BoldItalic TrueType WinAnsi yes yes no 144 0 BCDEEE+PalatinoLinotype-Bold TrueType WinAnsi yes yes no 157 0 BCDFEE+PalatinoLinotype-Roman TrueType WinAnsi yes yes no 161 0 BCDGEE+PalatinoLinotype-Italic TrueType WinAnsi yes yes no 165 0 BCDHEE+PalatinoLinotype-Roman CID TrueType Identity-H yes yes yes 169 0 BCDEEE+PalatinoLinotype-Bold TrueType WinAnsi yes yes no 181 0 BCDFEE+PalatinoLinotype-Roman TrueType WinAnsi yes yes no 185 0 BCDGEE+PalatinoLinotype-Italic TrueType WinAnsi yes yes no 189 0 BCDHEE+PalatinoLinotype-Roman CID TrueType Identity-H yes yes yes 193 0 BCDEEE+PalatinoLinotype-Bold TrueType WinAnsi yes yes no 212 0 BCDFEE+PalatinoLinotype-Roman TrueType WinAnsi yes yes no 216 0 BCDGEE+PalatinoLinotype-Italic TrueType WinAnsi yes yes no 220 0 BCDHEE+PalatinoLinotype-Roman CID TrueType Identity-H yes yes yes 224 0 Jhove (Rel. 1.22.1, 2019-04-17) Date: 2023-03-16 02:35:53 CET RepresentationInformation: pmc_35053327.pdf ReportingModule: PDF-hul, Rel. 1.12.1 (2019-04-17) LastModified: 2022-01-31 03:38:07 CET Size: 1984137 Format: PDF Version: 1.7 Status: Well-Formed and valid SignatureMatches: PDF-hul MIMEtype: application/pdf PDFMetadata: Objects: 405 FreeObjects: 1 IncrementalUpdates: 0 DocumentCatalog: PageLayout: SinglePage PageMode: UseNone Outlines: Item: Title: Introduction Destination: edu.harvard.hul.ois.jhove.module.pdf.PdfSimpleObject@44c8afef Item: Title: Materials and Methods Destination: edu.harvard.hul.ois.jhove.module.pdf.PdfSimpleObject@7b69c6ba Children: Item: Title: Participants and Samples Destination: edu.harvard.hul.ois.jhove.module.pdf.PdfSimpleObject@46daef40 Item: Title: Skin Biopsy and Processing Destination: edu.harvard.hul.ois.jhove.module.pdf.PdfSimpleObject@12f41634 Item: Title: Confocal Imaging and Measurements Destination: edu.harvard.hul.ois.jhove.module.pdf.PdfSimpleObject@13c27452 Item: Title: Intraepidermal Innervation and TDP-43 Nerve Colocalization Destination: edu.harvard.hul.ois.jhove.module.pdf.PdfSimpleObject@262b2c86 Item: Title: Data Analysis Destination: edu.harvard.hul.ois.jhove.module.pdf.PdfSimpleObject@371a67ec Item: Title: Results Destination: edu.harvard.hul.ois.jhove.module.pdf.PdfSimpleObject@5ed828d Children: Item: Title: TDP-43 Cytoplasmic Localization in ALS Patients Skin Biopsies Destination: edu.harvard.hul.ois.jhove.module.pdf.PdfSimpleObject@50d0686 Item: Title: TDP-43 Changes over Time Destination: edu.harvard.hul.ois.jhove.module.pdf.PdfSimpleObject@7a3d45bd Item: Title: TDP-43 and Epidermal Nerve Fibers Destination: edu.harvard.hul.ois.jhove.module.pdf.PdfSimpleObject@1e7c7811 Item: Title: Discussion Destination: edu.harvard.hul.ois.jhove.module.pdf.PdfSimpleObject@77ec78b9 Item: Title: References Destination: edu.harvard.hul.ois.jhove.module.pdf.PdfSimpleObject@1a3869f4 Info: Title: TDP-43 Cytoplasmic Translocation in the Skin Fibroblasts of ALS Patients Author: Miguel A. Rubio, Mireia Herrando-Grabulosa, Roser Velasco, Israel Blasco, Monica Povedano and Xavier Navarro Subject: 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. 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