ALS Overview
Amyotrophic lateral sclerosis (ALS) is a fatal neurodegenerative disorder characterized by progressive motor neuron loss. In most cases, pathology centers on TAR DNA-binding protein 43 (TDP-43), which mislocalizes from the nucleus to the cytoplasm and aggregates into insoluble structures. This dual effect drives both loss of nuclear RNA-binding function and gain of toxic cytoplasmic function, making TDP-43 aggregation a defining hallmark of ALS (Suk et al.).
ALS affects approximately 300,000 people annually worldwide. Diagnosis typically occurs in mid-to-late adulthood, with an average delay of 8-15 months between symptom onset and confirmed diagnosis (Spence et al.). By diagnosis, patients often exhibit neuropathological stage 1 or 2 of TDP-43 progression, affecting motor cortex, spinal cord, and brainstem nuclei, with early spread to prefrontal or striatal regions (Spence et al.). Mortality most often results from respiratory failure due to progressive paralysis, with average survival following diagnosis of 2-5 years (Spence et al.).
Central to ALS pathology is liquid-liquid phase separation (LLPS) in stress granules. Under cellular stress, TDP-43 concentrates into a liquid-like formation, which under oxidative stress transitions to solid aggregates (demixing). This event seeds pathology, but blocking demixing prevents TDP-43 aggregation in neuronal systems, highlighting a potential therapeutic intervention point (Yan et al.).
TDP-43 Pathology and Stress Granules
TDP-43 aggregation arises through its liquid-to-solid transition within stress granules. Normally, stress granules protect RNAs under transient stress, but chronic stress or TDP-43 mutations promote irreversible solidification. These aggregates impair nuclear RNA-binding functions while exerting toxic effects in the cytoplasm.
This pathological mechanism is not unique to ALS; liquid-to-solid transitions of RNA-binding proteins occur across multiple neurodegenerative diseases. Understanding these dynamics provides insights for targeted interventions beyond ALS.
RNA aptamers are promising tools for modulating TDP-43 behavior. Aptamers are short nucleic acids that fold into specific structures capable of high-affinity, selective binding. They can stabilize TDP-43 in its liquid-like state, preventing pathological aggregation (Yan et al.). Aptamers can serve as diagnostics by detecting early pathological conformers or therapeutics by preventing aggregation, offering a dual “theranostic” function.
Therapeutic Challenges and Opportunities
Current FDA-approved therapies, Riluzole and Edaravone, only modestly slow disease progression by targeting excitotoxicity and oxidative stress. They do not prevent TDP-43 aggregation, leaving the underlying pathology unaddressed.
Aptamer-based strategies provide a novel approach. By selectively binding TDP-43 within stress granules, aptamers can prevent demixing and pathological aggregate formation. These molecules offer a potential avenue for early intervention, with applications in both diagnostics and therapeutics, collectively termed “theranostics.”
Future research must tackle challenges such as aptamer stability in vivo, efficient neuronal delivery, and precise identification of TDP-43 binding domains. Despite these hurdles, RNA aptamers represent a promising frontier for halting ALS pathology at its earliest stages.
Conclusion
ALS is a devastating neurodegenerative disease primarily driven by TDP-43 aggregation through stress granule liquid-to-solid transitions. Existing therapies only slow progression, underscoring the need for interventions targeting early molecular events. RNA aptamers have emerged as a promising theranostic tool capable of preventing TDP-43 aggregation while enabling early disease detection. Advancing these approaches could reshape ALS treatment and offer insights applicable to broader neurodegenerative diseases.
Works Cited
“Andy, David and Jik Have Led a New Study Published in Cell.” Hymanlab.org, 2025, https://hymanlab.org/blog/2025/andy-has-led-a-new-study-published-in-cell/
Spence, Holly, et al. “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.” Acta Neuropathologica, vol. 147, no. 1, Springer Science+Business Media, Mar. 2024, https://doi.org/10.1007/s00401-024-02705-1
Suk, Terry R., et al. “A Stress-Dependent TDP-43 SUMOylation Program Preserves Neuronal Function.” Molecular Neurodegeneration, vol. 20, no. 1, BioMed Central, Mar. 2025, https://doi.org/10.1186/s13024-025-00826-z
Yan, Xiao, et al. “Intra-Condensate Demixing of TDP-43 inside Stress Granules Generates Pathological Aggregates.” Cell, Cell Press, May 2025, https://doi.org/10.1016/j.cell.2025.04.039