Peer-reviewedCC BY-NC-ND 4.0Cell Reports Medicine
Anti-HDGFL2 cryptic protein antibodies provide a sensitive readout of TDP-43 pathology and clinical disease features
9 affiliations
- 1Neuroscience Institute, University of Miami Miller School of Medicine, Miami, FL 33136, USA
- 2Department of Biochemistry & Molecular Biology, University of Miami, Miami, FL 33136, USA
- 3Department of Neuroscience, Mayo Clinic, Jacksonville, FL 32224, USA
- 4Banner Sun Health Research Institute, Sun City, AZ 85351, USA
- 5Department of Neurology, Mayo Clinic, Jacksonville, FL 32224, USA
- 6Department of Neurology, Mayo Clinic, Rochester, MN 55905, USA
- 7Department of Neurology, University of California, San Francisco, San Francisco, CA 91358, USA
- 8Banner Alzheimer’s Institute, University of Arizona, Phoenix, AZ 85006, USA
- 9Department of Neurology, University of Miami, Miami, FL 33136, USA
Abstract
TAR DNA-binding protein (TDP-43) cytoplasmic aggregates and nuclear depletion contribute to TDP-43 dysfunction in frontotemporal lobar degeneration with TDP-43 pathology (FTLD-TDP) and forms of motor neuron disease (MND), particularly amyotrophic lateral sclerosis (ALS). TDP-43 regulates alternative splicing, but its dysfunction can engender the inclusion of cryptic exons (CEs) during splicing. Transcripts harboring an in-frame CE can generate de novo proteins. One example is the CE variant of hepatoma-derived growth factor-like protein 2 (HDGFL2-CE). To understand HDGFL2-CE as a readout of TDP-43 dysfunction, and its spatial relationship with TDP-43 pathology, we generate anti-HDGFL2-CE polyclonal and monoclonal antibodies and develop sensitive HDGFL2-CE immunoassays. With these tools, we observe that HDGFL2-CE accumulates in neurons with TDP-43 pathology, and that higher frontal cortex HDGFL2-CE in FTLD-TDP and FTLD-TDP/MND associates with greater pathological TDP-43, earlier age of onset, and shorter survival, supporting HDGFL2-CE as a marker tightly linked to TDP-43 dysfunction and clinical disease features.
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BibTeX
@article{citrano2026antihdgfl2,
title = {{Anti-HDGFL2 cryptic protein antibodies provide a sensitive readout of TDP-43 pathology and clinical disease features}},
author = {Kathryn J. Citrano and Vidhya Bharathi Maheswari Jawahar and Madison M. Reeves and Leonardo Petrucelli and Yari Carlomagno and Mei Yue and Jorge Alaiz Noya and Lillian M. Daughrity and Raul Baena Tomé and Karen Jansen-West and Bailey Rawlinson and Michael DeTure and Erica Engelberg-Cook and Alpana Singh and Neill R. Graff-Radford and Gregory S. Day and Bradley F. Boeve and Adam L. Boxer and David S. Knopman and Keith A. Josephs and Ronald C. Petersen and Björn Oskarsson and Nicholas J. Ashton and Dennis W. Dickson and Tania F. Gendron and Mercedes Prudencio and Yong-Jie Zhang and Leonard Petrucelli},
journal = {Cell Reports Medicine},
year = {2026},
month = oct,
doi = {10.1016/j.xcrm.2026.103105},
url = {https://doi.org/10.1016/j.xcrm.2026.103105},
note = {CC BY-NC-ND 4.0},
}
RIS
TY - JOUR
TI - Anti-HDGFL2 cryptic protein antibodies provide a sensitive readout of TDP-43 pathology and clinical disease features
AU - Kathryn J. Citrano
AU - Vidhya Bharathi Maheswari Jawahar
AU - Madison M. Reeves
AU - Leonardo Petrucelli
AU - Yari Carlomagno
AU - Mei Yue
AU - Jorge Alaiz Noya
AU - Lillian M. Daughrity
AU - Raul Baena Tomé
AU - Karen Jansen-West
AU - Bailey Rawlinson
AU - Michael DeTure
AU - Erica Engelberg-Cook
AU - Alpana Singh
AU - Neill R. Graff-Radford
AU - Gregory S. Day
AU - Bradley F. Boeve
AU - Adam L. Boxer
AU - David S. Knopman
AU - Keith A. Josephs
AU - Ronald C. Petersen
AU - Björn Oskarsson
AU - Nicholas J. Ashton
AU - Dennis W. Dickson
AU - Tania F. Gendron
AU - Mercedes Prudencio
AU - Yong-Jie Zhang
AU - Leonard Petrucelli
PY - 2026
DA - 2026/10/09
JO - Cell Reports Medicine
DO - 10.1016/j.xcrm.2026.103105
UR - https://doi.org/10.1016/j.xcrm.2026.103105
AB - TAR DNA-binding protein (TDP-43) cytoplasmic aggregates and nuclear depletion contribute to TDP-43 dysfunction in frontotemporal lobar degeneration with TDP-43 pathology (FTLD-TDP) and forms of motor neuron disease (MND), particularly amyotrophic lateral sclerosis (ALS). TDP-43 regulates alternative splicing, but its dysfunction can engender the inclusion of cryptic exons (CEs) during splicing. Transcripts harboring an in-frame CE can generate de novo proteins. One example is the CE variant of hepatoma-derived growth factor-like protein 2 (HDGFL2-CE). To understand HDGFL2-CE as a readout of TDP-43 dysfunction, and its spatial relationship with TDP-43 pathology, we generate anti-HDGFL2-CE polyclonal and monoclonal antibodies and develop sensitive HDGFL2-CE immunoassays. With these tools, we observe that HDGFL2-CE accumulates in neurons with TDP-43 pathology, and that higher frontal cortex HDGFL2-CE in FTLD-TDP and FTLD-TDP/MND associates with greater pathological TDP-43, earlier age of onset, and shorter survival, supporting HDGFL2-CE as a marker tightly linked to TDP-43 dysfunction and clinical disease features.
SN - 2666-3791
ER -