A test that detects signs of motor neurone disease (MND) before symptoms appear has been hailed a “game changer” by scientists developing it, who say spotting the incurable condition at its earliest stages will open the door for more effective treatments.
The tool, known as TDP-43 aptamer, is able to detect damaged cell proteins in brain tissue samples. These proteins, said the researchers, are indicators, or biomarkers, of MND that can be spotted before cells begin to malfunction and symptoms start to appear.
Dr Holly Spence, from the University of Aberdeen, said: “Our findings have implications for early diagnostics and intervention before symptom onset in MND.
“With better ability to detect disease, we might be able to diagnose people with MND earlier, when therapeutic drugs might be much more effective.”
The Independent reports that although there’s no cure for MND, treatments can help reduce its impact on a person’s daily life.
It is caused by a build-up of certain proteins in the brain that clump together, causing the cells to gradually stop working.
Symptoms include impaired movement, thinking and breathing, which worsens over time.
The “aptamer” lab test works by identifying abnormal protein clumps in a brain tissue sample taken from a patient during a biopsy.
The researchers said their test could pick up indicators of MND earlier and with more sensitivity than methods currently used.
Dr Jenna Gregory, from the University of Aberdeen, said: “This tool ‘targets’ the disease protein and allows us to see where toxic clumps are building up in the body.
“It can do this for much lower amounts of disease proteins, and with greater accuracy than ever before. This could be a game changer for MND research, diagnostics and treatment.”
The research was funded by Target ALS and is published in the journal Acta Neuropathologica.
Commenting on the research, Dr Brian Dickie, director of research at the Motor Neurone Disease Association, said: “It often takes a year from the first onset of symptoms to receiving a diagnosis of MND.
“This innovative research into the early cellular changes occurring in MND offers exciting potential for the development of new tests to help reduce diagnostic delay.
“As treatment does not begin until the disease is diagnosed, earlier intervention will hopefully also mean that treatments are more effective.”
Study details
RNA aptamer reveals nuclear TDP-43 pathology is an early aggregation event that coincides with STMN-2 cryptic splicing and precedes clinical manifestation in ALS
Holly Spence, Fergal Waldron, Jenna Gregory et al.
Published in Acta Neuropathologica on 5 March 2024
Abstract
TDP-43 is an aggregation-prone protein which accumulates in the hallmark pathological inclusions of amyotrophic lateral sclerosis (ALS). However, the analysis of deeply phenotyped human post-mortem samples has shown that TDP-43 aggregation, revealed by standard antibody methods, correlates poorly with symptom manifestation. Recent identification of cryptic-splicing events, such as the detection of Stathmin-2 (STMN-2) cryptic exons, are providing evidence implicating TDP-43 loss-of-function as a potential driving pathomechanism but the temporal nature of TDP-43 loss and its relation to the disease process and clinical phenotype is not known. To address these outstanding questions, we used a novel RNA aptamer, TDP-43APT, to detect TDP-43 pathology and used single molecule in situ hybridisation to sensitively reveal TDP-43 loss-of-function and applied these in a deeply phenotyped human post-mortem tissue cohort. We demonstrate that TDP-43APT identifies pathological TDP-43, detecting aggregation events that cannot be detected by classical antibody stains. We show that nuclear TDP-43 pathology is an early event, occurring prior to cytoplasmic accumulation and is associated with loss-of-function measured by coincident STMN-2 cryptic splicing pathology. Crucially, we show that these pathological features of TDP-43 loss-of-function precede the clinical inflection point and are not required for region specific clinical manifestation. Furthermore, we demonstrate that gain-of-function in the form of extensive cytoplasmic accumulation, but not loss-of-function, is the primary molecular correlate of clinical manifestation. Taken together, our findings demonstrate implications for early diagnostics as the presence of STMN-2 cryptic exons and early TDP-43 aggregation events could be detected prior to symptom onset, holding promise for early intervention in ALS.
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