The human-specific lncRNA HD-LINC drives lipid droplet-associated neurodegeneration in Huntington's disease

HD-LINC (LINC01139) is selectively induced in symptomatic Huntington’s disease patient-derived MSNs and human HD caudate, and its modulation strongly alters neuritic lipid droplet pathology and degeneration.

• Why it matters: Human-specific regulatory mechanisms linked to striatal medium spiny neuron vulnerability in Huntington’s disease remain unclear, limiting therapeutic targets.
• What they did: Single-cell transcriptomics identified HD-LINC enrichment in a symptomatic HD neuronal state; reducing HD-LINC attenuated mutant HTT aggregation, dystrophic neurites, DNA damage, and neuronal death, while overexpression exacerbated them, and lipidomic/transcriptomic analyses implicated neuronal lipid regulation.
• The result: HD-MSNs showed enlarged, low-mobility neuritic lipid droplets with increased lipid peroxidation; HD-LINC knockdown cleared neuritic LD accumulation and reduced lipid peroxidation, and antisense oligonucleotides reduced HD-LINC and reversed HD-LINC-associated phenotypes.