Functional roles and networks of non-coding RNAs in the pathogenesis of neurodegenerative diseases

Abstract

Recent transcriptome analyses have revealed that noncoding RNAs (ncRNAs) are broadly expressed in mammalian cells and abundant in the CNS, with tissue and cell type-specific expression patterns. Moreover, ncRNAs have been found to intricately and dynamically regulate various signaling pathways in neurodegeneration. As such, some antisense transcripts and microRNAs are known to directly affect neurodegeneration in disease contexts. The functions of ncRNAs in pathogenesis are unique for each disorder, as are the pertinent networks of ncRNA/miRNA/mRNA that mediate these functions. Thus, further understanding of ncRNA biogenesis and effects might aid the discovery of diagnostic biomarkers or development of effective therapeutics for neurodegenerative disorders. Here, we review the ncRNAs that have so far been identified in major neurodegenerative disease etiology and the mechanisms that link ncRNAs with disease-specific phenotypes, such as HTT aggregation in HD, α-synuclein in PD, and Aβ plaques and hyperphosphorylated Tau in AD. We also summarize the known lncRNA/miRNA/mRNA networks that participate in neurodegenerative diseases, and we discuss ncRNA-related treatments shown to delay disease onset and prolong lifespan in rodent models.

Keywords: Alzheimer’s disease (AD); Central nervous system (CNS); Huntington’s disease (HD); Long non-coding RNAs (lncRNAs); MicroRNAs (miRNAs); Motor neuron diseases; Neurodegenerative diseases; Noncoding RNAs (ncRNAs); Parkinson’s disease (PD).

Fig. 1

Cellular functions of ncRNAs involved in HD pathogenesis. (a) LncRNAs regulate mutant Htt induced neurotoxicity. (b) Networks of mutant Htt, microRNAs and mRNAs regulate neurotoxicity in HD. LncRNAs are shown in red, mRNA are shown in green and microRNAs are shown in blue

Fig. 2

Cellular functions of ncRNAs involved in PD pathogenesis. (a) ncRNAs affect α-synuclein formation, which is linked to loss of dopaminergic (DA) neurons. (b) ncRNAs regulate apoptotic pathways leading to DA neuron degeneration. (c) ncRNAs regulate mitochondrial dysfunction. (d) ncRNAs regulates DA neuron viability

Fig. 3

ncRNAs involved in APP expression and Aβ accumulation in AD. (a) ncRNAs promote APP expression (b) ncRNAs promote Aβ accumulation. (c) ncRNAs regulate BACE-1 function and Aβ secretion

Fig. 4

Cellular functions of ncRNAs that regulate pTau and cell death in AD pathogenesis. (a) ncRNAs promote kinase activity and pTau accumulation. (b) ncRNAs promote cellular pathways leading to neurodegeneration in AD