Up-regulation of LINC00520 in in vitro models of Parkinson's disease: searching for a physiological role and dysregulation in neurodegeneration

The central nervous system (CNS) expresses a large number of long non-coding RNAs (lncRNAs), non-protein coding transcripts longer than 200 nucleotides, which are important for numerous physiological processes like brain development and neural functioning. Notably, their dysregulation has been demonstrated in several neurodegenerative disorders, including Parkinson's disease (PD). The hallmark of PD is the depletion of dopaminergic neurons in the substantia nigra pars compacta (SNpc) and the accumulation of cytoplasmic inclusion of a-synuclein (Lewy bodies). The neurotoxic phenotype of activated microglia contributes to PD pathogenesis by worsening inflammatory processes and exposing neurons to oxidative stress. Interestingly, we identified a disrupted expression of some lncRNAs through a meta-analysis by comparing transcriptomic data of PD patients vs control brain samples. In particular, LINC00520, which had not previously been connected to PD, showed a marked up-regulation. Our aim is to validate the results of the meta-analysis and characterize its pathophysiological role in different in vitro models. We looked at LINC00520 expression in the human neuroblastoma SH-SY5Y cells, treated with 6-OHDA to elicit an oxidative stress response, and in human monocytic THP-1 cells differentiated towards microglial-like fate with PMA and activated with LPS. Then, we included the human microglia cell line HMC3 that had been exposed to 6-OHDA or Rotenone as well as IFNg-boosted by glucose to increase the NF-kB inflammatory pathway. Our results showed a significant upregulation of LINC00520 in all in vitro PD models. Moreover, preliminary results of RNAi assays suggested that LINC00520 was involved in oxidative stress-related pathways. We also identified a potential LINC00520 ortholog in zebrafish, ZFLNCG09760, whose sequencing and functional characterization are still ongoing.