Title:The Long Non-Coding RNAs in Neurodegenerative Diseases: Novel Mechanisms of Pathogenesis
Volume: 13
Issue: 11
Author(s): Paola Riva, Antonia Ratti, Marco Venturin
Affiliation:
关键词:
lncRNA、lncRNA细胞质活动、lncRNA核活动、神经退行性疾病、发病的机制、转录后调节。
摘要: Background: Long-non-coding RNAs (lncRNAs), RNA molecules longer than 200 nucleotides,
have been involved in several biological processes and in a growing number of diseases, controlling
gene transcription, pre-mRNA processing, the transport of mature mRNAs to specific cellular
compartments, the regulation of mRNA stability, protein translation and turnover. The fundamental role
of lncRNAs in central nervous system (CNS) is becoming increasingly evident. LncRNAs are abundantly
expressed in mammalian CNS in a specific spatio-temporal manner allowing a quick response to
environmental/molecular changes.
Methods: This article reviews the biology and mechanisms of action of lncRNAs underlying their potential
role in CNS and in some neurodegenerative diseases.
Results: an increasing number of studies report on lncRNAs involvement in different molecular
mechanisms of gene expression modulation in CNS, from neural stem cell differentiation mainly by
chromatin remodeling, to control of neuronal activities. More recently, lncRNAs have been implicated
in neurodegenerative diseases, including Alzheimer’s Disease, where the role of BACE1-AS lncRNA
has been widely defined. BACE1-AS levels are up-regulated in AD brains where BACE1-AS acts by
stabilizing BACE1 mRNA thereby increasing BACE1 protein content and Aβ42 formation. In Frontotemporal
dementia and Amyotrophic lateral sclerosis the lncRNAs NEAT1_2 and MALAT1 co-localize
at nuclear paraspeckles with TDP-43 and FUS proteins and their binding to TDP-43 is markedly increased
in affected brains. In Parkinson’s Disease the lncRNA UCHL1-AS1 acts by directly promoting
translation of UCHL1 protein leading to perturbation of the ubiquitin-proteasome system. Different
lncRNAs, such as HTT-AS, BDNF-AS and HAR1, were found to be dysregulated in their expression
also in Huntington’s Disease. In Fragile X syndrome (FXS) and Fragile X tremor/ataxia syndrome
(FXTAS) patients, the presence of CGG repeats expansion alters the expression of the lncRNAs
FMR1-AS1 and FMR6. Interestingly, they are expressed in peripheral blood leukocytes, suggesting
these lncRNAs may represent biomarkers for FXS/FXTAS early detection and therapy. Finally, the
identification of the antisense RNAs SCAANT1-AS and ATXN8OS in spinocerebellar ataxia 7 and 8, respectively,
suggests that very different mechanisms of action driven by lncRNAs may trigger neurodegeneration
in these disorders.
Conclusion: The emerging role of lncRNAs in neurodegenerative diseases suggests that their dysregulation
could trigger neuronal death via still unexplored RNA-based regulatory mechanisms which
deserve further investigation. The evaluation of their diagnostic significance and therapeutic potential
could also address the setting up of novel treatments in diseases where no cure is available to date.
