C9ORF72's Role in Neuroinflammation: New ALS and FTD Insights

Limone F, Couto A, Wang JY, Zhang Y, McCourt B, Huang C, Minkin A, Jani M, McNeer S, Keaney J, Gillet G, Gonzalez RL, Goodman WA, Kadiu I, Eggan K, Burberry A. Myeloid and lymphoid expression of C9orf72 regulates IL-17A signaling in mice. Sci Transl Med. 2024 Jan 31;16(732):eadg7895. doi: 10.1126/scitranslmed.adg7895. Epub 2024 Jan 31. PMID: 38295187.

Summary

This study led by the laboratories of Drs. Aaron Burberry and Kevin Eggan demonstrates the significant role of C9orf72 in regulating IL-17A signaling and neuroinflammation in ALS and FTD. The study, focusing on mouse models, reveals how myeloid and lymphoid expression of C9orf72 influences autoimmune responses, potentially contributing to the onset of neurological symptoms. The findings underscore the importance of C9orf72 in neuroinflammatory pathways, offering new perspectives for understanding and treating ALS and FTD.

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Early ALS/FTD Detection Using Biomarkers Reporting on TDP-43 Splicing Changes

Irwin KE, Jasin P, Braunstein KE, Sinha IR, Garret MA, Bowden KD, Chang K, Troncoso JC, Moghekar A, Oh ES, Raitcheva D, Bartlett D, Miller T, Berry JD, Traynor BJ, Ling JP, Wong PC. A fluid biomarker reveals loss of TDP-43 splicing repression in presymptomatic ALS-FTD. Nat Med. 2024 Jan 26. doi: 10.1038/s41591-023-02788-5. Epub ahead of print. PMID: 38278991.

Summary

This study from a team of researchers led by Dr. Phil Wong unveils a novel biomarker for early detection of amyotrophic lateral sclerosis (ALS) and frontotemporal dementia (FTD). It focuses on the loss of TDP-43 splicing repression, a key molecular change observed presymptomatically in ALS-FTD. Researchers developed a sensitive assay detecting the cryptic neoepitope in blood and cerebrospinal fluid, enabling earlier diagnosis and potentially improving clinical trial recruitment and monitoring. This breakthrough may significantly impact the understanding and management of ALS-FTD.

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PD-Linked Misfolded Alpha-Synuclein Identified in a Subset of ALS Patients CSF

Smith R, Hovren H, Bowser R, Bakkar N, Garruto R, Ludolph A, Ravits J, Gaertner L, Murphy D, Lebovitz R. Misfolded alpha-synuclein in amyotrophic lateral sclerosis: Implications for diagnosis and treatment. Eur J Neurol. 2024 Jan 25:e16206. doi: 10.1111/ene.16206. Epub ahead of print. PMID: 38270442.

Summary

Drs. Richard Smith and Russ Lebovitz lead a team of researchers investigating the role of misfolded alpha-synuclein (α-Syn) in amyotrophic lateral sclerosis (ALS). Researchers used a seed amplification assay to detect toxic α-Syn in the spinal fluid of ALS patients, including familial, sporadic, and Guamanian variants. The presence of α-Syn was identified in a significant subset of ALS cases. This groundbreaking finding suggests that α-Syn may contribute to ALS pathogenesis, opening new avenues for diagnosis and treatment strategies targeting this specific subgroup of ALS patients.

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