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New research indicates that gut bacteria might contribute to inflammation in ALS and FTD linked to C9ORF72 mutations.

Scientists identified 10 distinct bacterial strains that induced macrophage cytokine release in a C9orf72-dependent manner, suggesting that the microbiome is an active factor in disease risk. A key discovery was the bacterial glycogen biosynthesis, which distinguished commensals capable of triggering inflammatory responses. This provided the researchers with a clearer explanation of how gut dysbiosis might influence neurodegeneration. In germ-free C9orf72-deficient mice, colonization with glycogen-producing Parabacteroides merdae increased immune activation, BBB breakdown, and T cell infiltration into the CNS. Breaking down glycogen in the gut improved survival and decreased brain inflammation, while human stool samples showed inflammatory glycogen enrichment in many ALS and C9ORF72-FTD cases, highlighting bacterial glycogen as a modifiable gut-brain target.

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https://www.cell.com/cell-reports/fulltext/S2211-1247(25)01678-X?_returnURL=https%3A%2F%2Flinkinghub.elsevier.com%2Fretrieve%2Fpii%2FS221112472501678X%3Fshowall%3Dtrue

Targeted modifications in how mutant huntingtin is marked for removal may significantly affect Huntington disease (HD) progression.

Using knock-in mouse models, researchers discovered that preventing ubiquitination at lysines 6 and 9 reduced the efficient clearance of mutant huntingtin, resulting in increased buildup of both soluble and aggregated forms of the protein. The altered protein increasingly accumulated in neuronal nuclei, formed larger inclusion bodies, and accelerated motor decline, brain atrophy, and worsening neuropathology. This indicates that even highly specific disruptions in the cell’s protein quality-control system can greatly impact disease severity. These findings demonstrate that ubiquitination at K6 and K9 is not just a minor molecular detail but a critical regulator of where mutant huntingtin gathers and how toxic it becomes, emphasizing site-specific ubiquitination as a promising therapeutic target for reducing neuronal damage and HD disease progression.

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https://www.pnas.org/doi/10.1073/pnas.2527258122