A groundbreaking study from the National Institute on Aging (NIA) has identified a promising fluid biomarker with the potential to detect two neurodegenerative conditions, amyotrophic lateral sclerosis (ALS) and frontotemporal dementia (FTD), even before clinical symptoms manifest. Published in the prestigious journal Nature Medicine, this research revealed that the innovative test can discern molecular hallmarks indicative of ALS and FTD, paving the way for early diagnosis and intervention.
At the heart of the matter is a protein known as TDP-43, which, in healthy brain cells, is typically localized within the cell nucleus — the compartment that houses DNA. However, in individuals afflicted with ALS and FTD, an aberrant accumulation of TDP-43 is observed in the cell’s cytoplasm, the area outside the nucleus. This misplacement leads to a shortage of TDP-43 in the nucleus and triggers a cascade of alterations in gene expression and protein synthesis.
The role of genes in the life of a cell is akin to a set of blueprints for constructing proteins, the cell’s workhorses. These blueprints, known as exons when referring to segments of DNA, are read in a versatile fashion, allowing for a myriad of protein variants to be synthesized. TDP-43 exerts influence over this reading process, guiding which exons are chosen to assemble the complete protein. Typically, the binding of TDP-43 to a specific exon signals for its exclusion from the final protein product. This new test, then, offers a window into these fundamental cellular mechanisms, promising a leap forward in how we approach neurodegenerative diseases.
In individuals with ALS and FTD, the protein TDP-43 becomes depleted from the nucleus, leading to the production of proteins that include normally absent segments, known as cryptic exons. Researchers from the National Institute on Aging (NIA), National Institute of Neurological Disorders and Stroke (NINDS), Johns Hopkins University School of Medicine, and other collaborative agencies have forged a novel method to detect these cryptic exons, propelling it as a prospective diagnostic biomarker for certain neurodegenerative diseases.
The team engineered antibodies designed to target proteins formed from the cryptic exons anticipated in cells with diminished nucleus-based TDP-43. While antibodies are known for their defense in the immune system, they are likewise invaluable tools for scientists, due to their capacity to latch onto specific molecules. The study showcased that the antibody tailored to a protein containing a cryptic exon from the HDGFL2 gene was notably effective in cell culture trials.
Leveraging this antibody, the researchers designed a laboratory test applicable to human blood and cerebrospinal fluid samples. When the HDGFL2-derived protein is detected in a patient’s sample, it triggers an electrochemical luminescent signal that can be captured using specialized imaging equipment. This lab test demonstrated a high level of precision in identifying the cryptic exons within samples from individuals with a hereditary form of ALS and FTD, even prior to the onset of symptoms. Intriguingly, the assay detected heightened levels of the HDGFL2 cryptic exon protein in cerebrospinal fluid samples from patients with non-genetic ALS.
The findings from this investigatory study illuminate the potential of employing HDGFL2 cryptic exon detection as a diagnostic avenue for nascent ALS and FTD. Probing into the future, there is an anticipation to explore whether heightened levels of HDGFL2 cryptic exons in cerebrospinal fluid or blood are indicative of a heightened risk for developing ALS and FTD in cases devoid of genetic predispositions. Further research stands poised to assess the efficacy of this diagnostic tool in the context of other conditions wherein TDP-43 plays a pivotal role, including Alzheimer’s disease, multiple sclerosis, chronic traumatic encephalopathy, and limbic predominant age-related TDP-43 encephalopathy. An earlier diagnosis facilitated by these methods could present the opportunity for timely and potentially more effective therapeutic interventions.