The long noncoding RNA neuroLNC regulates presynaptic activity by interacting with the neurodegeneration-associated protein TDP-43

Abstract

The cellular and the molecular mechanisms by which long noncoding RNAs (lncRNAs) may regulate presynaptic function and neuronal activity are largely unexplored. Here, we established an integrated screening strategy to discover lncRNAs implicated in neurotransmitter and synaptic vesicle release. With this approach, we identified neuroLNC, a neuron-specific nuclear lncRNA conserved from rodents to humans. NeuroLNC is tuned by synaptic activity and influences several other essential aspects of neuronal development including calcium influx, neuritogenesis, and neuronal migration in vivo. We defined the molecular interactors of neuroLNC in detail using chromatin isolation by RNA purification, RNA interactome analysis, and protein mass spectrometry. We found that the effects of neuroLNC on synaptic vesicle release require interaction with the RNA-binding protein TDP-43 (TAR DNA binding protein-43) and the selective stabilization of mRNAs encoding for presynaptic proteins. These results provide the first proof of an lncRNA that orchestrates neuronal excitability by influencing presynaptic function.

LncRNA PVT1 promotes gemcitabine resistance of pancreatic cancer via activating Wnt/β-catenin and autophagy pathway through modulating the miR-619-5p/Pygo2 and miR-619-5p/ATG14 axes

“…LncRNAs have been reported to exert their biological functions by interacting with certain proteins [ 30 ]. Interestingly, PVT1 was predicted to bind ATG14 using the online alignment tool RPISeq ( http://pridb.gdcb.iastate.edu//RPISeq/ ) [ 31 ].…”

The functions of N6-methyladenosine modification in lncRNAs

“…Increasing evidence indicates that lncRNAs play key roles in gene regulation and disease processes. 1 , 2 , 3 , 4 , 5 , 6 It has been demonstrated that lncRNAs mediate gene regulation through binding with DNA, RNA, or proteins. 7 , 8 , 9 , 10 For example, lncRNAs may act as signals or decoys of transcription, as protein scaffolds, or as epigenetic regulators.…”

Non-Coding RNAs as Sensors of Oxidative Stress in Neurodegenerative Diseases

“…Forty percent of described lncRNAs have been reported in the CNS [102], where they participate in gene expression, imprinting and pluripotency regulation, as reported by numerous studies [103][104][105][106]. One of the first described lncRNAs was H19, a paternally imprinted gene, whose importance in embryonic development and neural viability has been established [107].…”

“…NeuroLNC, a nuclear lncRNA, has been recently involved in synapsis establishment. Its interaction with the well-known RNA-binding protein TDP-43 appears to be essential for the correct release of neurotransmitters [106]. In addition, RMST1 functions as a guide-RNA for SOX2 transcription factor towards neurogenic genes [110] promoting neural differentiation although it is also expressed in astrocytes [111].…”