Pharmaco-genetic evidence of presymptomatic lysosomal dysfunction coupled to detrimental DPR secretion in Drosophila Models of C9orf72-linked ALS/FTD.

In Drosophila melanogaster expressing toxic C9orf72 repeats, presymptomatic lysosome impairment is linked to detrimental DPR secretion, with valproic acid partially preventing neurodegenerative and locomotor phenotypes.

• Why it matters: Autophagy-lysosome pathway disruption is implicated in C9orf72 ALS/FTD, but the specific role of lysosomal dysfunction in disease progression—especially how it affects DPR release—remains unclear.
• What they did: The study used a Drosophila melanogaster model expressing toxic C9orf72 repeats, then tested valproic acid effects in the presence of Mitf and applied genetic inhibition or downregulation of lysosomal degradation, autophagy, and secretory autophagy genes.
• The result: Disabling lysosome function increased neuronal release of autophagy-associated proteins and DPRs (not autophagy induction), and these were taken up by nearby neurons and glia in vivo, supporting secretion-linked propagation.

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