Anti-HDGFL2 cryptic protein antibodies provide a sensitive readout of TDP-43 pathology and clinical disease features.

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.