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

Huntington's disease (HD) is characterized by degeneration of striatal medium spiny neurons (MSNs), yet the human-specific regulatory mechanisms that contribute to neuronal vulnerability remain poorly understood. Here, we identify HD-LINC (LINC01139), a human-specific long intergenic noncoding RNA selectively induced in symptomatic HD patient-derived MSNs (HD-MSNs) and human HD caudate. Single-cell transcriptomic analysis in HD-MSNs revealed that HD-LINC was enriched in a symptomatic HD neuronal state associated with lipid metabolic and protein clearance regulation, while not observed in non-degenerative reprogrammed MSNs derived from pre-manifest HD individuals. Reducing HD-LINC attenuated mutant HTT aggregation, dystrophic neurites, DNA damage, and neuronal death, whereas HD-LINC overexpression exacerbated these phenotypes. Transcriptomic and lipidomic analyses further implicated HD-LINC in neuronal lipid regulation. We found that HD-MSNs exhibited aberrant accumulation of enlarged, low-mobility lipid droplets (LDs) within neurites, a previously unrecognized phenotype in patient-derived neurons. Critically, increased lipid peroxidation was observed within LD-enriched dystrophic neurites in HD-MSNs. HD-LINC knockdown cleared neuritic LD accumulation, restored soma-enriched LD distribution, and reduced lipid peroxidation. Finally, we developed antisense oligonucleotides that effectively reduced HD-LINC and reversed HD-LINC-associated phenotypes, nominating HD-LINC lowering as a potential therapeutic strategy in HD. These results identify HD-LINC as a human-specific regulator of neuronal LD spatial organization, lipid peroxidation, and neuronal degeneration in HD. They further reveal dysregulated neuritic LD accumulation driven by HD-LINC, and highlight lincRNA-mediated lipid dysregulation as a significant contributor to neuronal vulnerability to degeneration.