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    X-linked dystonia-parkinsonism is a rare neurological disease endemic to the Philippines. Dystonic symptoms appear in males at the mean age of 40 years and progress to parkinsonism with degenerative pathology in the striatum. A retrotransposon inserted in intron 32 of the TAF1 gene leads to alternative splicing in the region and a reduction of the full-length mRNA transcript. The objective of this study was to discover cell-based and biofluid-based biomarkers for X-linked dystonia-parkinsonism. RNA from patient-derived neural progenitor cells and their secreted extracellular vesicles were used to screen for dysregulation of TAF1 expression. Droplet-digital polymerase chain reaction was used to quantify the expression of TAF1 mRNA fragments 5' and 3' to the retrotransposon insertion and the disease-specific splice variant TAF1-32i in whole-blood RNA. Plasma levels of neurofilament light chain were measured using single-molecule array. In neural progenitor cells and their extracellular vesicles, we confirmed that the TAF1-3'/5' ratio was lower in patient samples, whereas TAF1-32i expression is higher relative to controls. In whole-blood RNA, both TAF1-3'/5' ratio and TAF1-32i expression can differentiate patient (n = 44) from control samples (n = 18) with high accuracy. Neurofilament light chain plasma levels were significantly elevated in patients (n = 43) compared with both carriers (n = 16) and controls (n = 21), with area under the curve of 0.79. TAF1 dysregulation in blood serves as a disease-specific biomarker that could be used as a readout for monitoring therapies targeting TAF1 splicing. Neurofilament light chain could be used in monitoring neurodegeneration and disease progression in patients. © 2020 The Authors. Movement Disorders published by Wiley Periodicals LLC on behalf of International Parkinson and Movement Disorder Society. © 2020 The Authors. Movement Disorders published by Wiley Periodicals LLC on behalf of International Parkinson and Movement Disorder Society.


    Jamal Al Ali, Christine A Vaine, Shivangi Shah, Lindsey Campion, Ahmad Hakoum, Melanie L Supnet, Patrick Acuña, Gabrielle Aldykiewicz, Trisha Multhaupt-Buell, Niecy G M Ganza, John B B Lagarde, Jan K De Guzman, Criscely Go, Benjamin Currall, Bianca Trombetta, Pia K Webb, Michael Talkowski, Steven E Arnold, Pike S Cheah, Naoto Ito, Nutan Sharma, D Cristopher Bragg, Laurie Ozelius, Xandra O Breakefield. TAF1 Transcripts and Neurofilament Light Chain as Biomarkers for X-linked Dystonia-Parkinsonism. Movement disorders : official journal of the Movement Disorder Society. 2021 Jan;36(1):206-215

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    PMID: 32975318

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