Searching for MIND: MicroRNAs in Neurodegenerative Diseases

Barbato, Christian; Ruberti, Francesca; Cogoni, Carlo

doi:10.1155/2009/871313

Cited by 42 publications

(41 citation statements)

References 43 publications

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“…Regulation of mitochondrial distribution is particularly important in neurons, whose extended processes are highly dependent on organelle transport to balance the changing energy needs of each portion of the cell and any disturbance could lead to neurodegeneration (20). microRNAs (miRNAs) have been defined as regulators of endogenous genes and their involvement in neurodegenerative diseases has been previously described (21)(22)(23)(24)(25). In HIV-1-infected cells, miRNAs have been shown to be conserved factors whose complete suppression is incompatible with cellular viability.…”

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confidence: 99%

Deregulation of microRNAs by HIV-1 Vpr Protein Leads to the Development of Neurocognitive Disorders

Mukerjee

Chang

Valle

et al. 2011

Journal of Biological Chemistry

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Studies have shown that HIV-infected patients develop neurocognitive disorders characterized by neuronal dysfunction.The lack of productive infection of neurons by HIV suggests that viral and cellular proteins, with neurotoxic activities, released from HIV-1-infected target cells can cause this neuronal deregulation. The viral protein R (Vpr), a protein encoded by HIV-1, has been shown to alter the expression of various important cytokines and inflammatory proteins in infected and uninfected cells; however the mechanisms involved remain unclear. Using a human neuronal cell line, we found that Vpr can be taken up by neurons causing: (i) deregulation of calcium homeostasis, (ii) endoplasmic reticulum-calcium release, (iii) activation of the oxidative stress pathway, (iv) mitochondrial dysfunction and vsynaptic retraction. In search for the cellular factors involved, we performed microRNAs and gene array assays using human neurons (primary cultures or cell line, SH-SY5Y) that we treated with recombinant Vpr proteins. Interestingly, Vpr deregulates the levels of several microRNAs (e.g. miR-34a) and their target genes (e.g. CREB), which could lead to neuronal dysfunctions. Therefore, we conclude that Vpr plays a major role in neuronal dysfunction through deregulating microRNAs and their target genes, a phenomenon that could lead to the development of neurocognitive disorders.Although effective in prolonging the life expectancy in patients with HIV infection (1), the highly active antiretroviral therapy (HAART) 2 in fact has resulted in an increased prevalence of HIV-associated neurocognitive disorders (HAND) (2). The molecular mechanisms leading to this phenomenon remain to be elucidated. Several reports indicated that HIVinfected macrophages and microglia produce neurotoxins (e.g. viral and cellular proteins) that have the ability to cause neuronal deregulation and to promote HAND (3, 4). The viral protein R (Vpr) is among the released HIV-1 proteins that have been considered to be deleterious to neurons; however the molecular mechanisms involved remain unclear (5-7). Vpr is packaged into the virion, and is essential for HIV-1 replication in macrophages (8, 9). Infected brain cells have been shown to release Vpr that could affects neuronal growth (10). Vpr mediates multiple functions, including nuclear import of the HIV-1 pre-integration complex, G 2 cell cycle arrest, transactivation of both viral replication, and host genes and induction of apoptosis (11,12). Vpr was also detected in a soluble form in CSF and sera of HIV-infected patients displaying neurological disorders (10). Vpr causes neuronal degeneration both in vitro and in vivo (7,10,13).A calcium channel is an ion channel, which displays selective permeability to Ca 2ϩ ions. It is sometimes synonymous as voltage-dependent Ca 2ϩ channel (VDCC) (14). Activation of particular VDCCs allows Ca 2ϩ entry into the cell, which depending on the cell type, results in muscular contraction, excitation of neurons, up-regulation of gene expression, or release of neuro...

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Deregulation of microRNAs by HIV-1 Vpr Protein Leads to the Development of Neurocognitive Disorders

Mukerjee

Chang

Valle

et al. 2011

Journal of Biological Chemistry

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“…In addition, microRNAs are recruited during the execution of neuronal signal transduction pathways (27). Emerging evidence suggests that changes in expression of microRNAs are associated with neurodegenerative diseases (28). Profiling microRNAs from selected human brain areas has revealed significant changes in AD patients (29 -31).…”

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MicroRNA-101 Regulates Amyloid Precursor Protein Expression in Hippocampal Neurons

Vilardo

Barbato

Ciotti

et al. 2010

Journal of Biological Chemistry

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141

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The amyloid precursor protein (APP) and its proteolytic product amyloid beta (A␤) are associated with both familial and sporadic forms of Alzheimer disease (AD). Aberrant expression and function of microRNAs has been observed in AD. Here, we show that in rat hippocampal neurons cultured in vitro, the down-regulation of Argonaute-2, a key component of the RNA-induced silencing complex, produced an increase in APP levels. Using site-directed mutagenesis, a microRNA responsive element (RE) for miR-101 was identified in the 3-untranslated region (UTR) of APP. The inhibition of endogenous miR-101 increased APP levels, whereas lentiviral-mediated miR-101 overexpression significantly reduced APP and A␤ load in hippocampal neurons. In addition, miR-101 contributed to the regulation of APP in response to the proinflammatory cytokine interleukin-1␤ (IL-l␤). Thus, miR-101 is a negative regulator of APP expression and affects the accumulation of A␤, suggesting a possible role for miR-101 in neuropathological conditions. Alzheimer disease (AD)2 is the most common form of dementia in aged individuals and is characterized by A␤ plaques, which contain A␤ aggregates and neurofibrillary tangles which consist primarily of aggregated forms of the microtubule-stabilizing protein tau (reviewed in Ref. 1). A␤ peptides are derived from processing of the type I transmembrane protein APP through sequential cleavages by ␤ and ␥ secretase (2-3). The A␤ load during pathology leads to neurological dysfunction. APP is linked to AD; familial AD can be caused by increased expression of APP due to either genomic duplication (4 -5) or regulatory sequence alterations (6). Among the physiological and pathological activators of APP expression (7-8) is the proinflammatory cytokine IL-1␤ (9). IL-1␤ is produced in the central nervous system (CNS) in response to damage and influences neuronal function by interacting with the type I IL-1 receptor expressed on neurons (10 -11). IL-1␤ is overexpressed in AD (12) and has been implicated in initiation and progression of AD pathology (13). In addition, IL-1␤ promotes APP transcription (14) and translation (9) in various cell types. Transcriptional and post-transcriptional regulation of APP expression has been widely studied and correlated to AD pathogenesis (15-16). Both cell type-specific promoter elements (17) and regulatory elements in the 5Ј-and 3Ј-UTRs of APP mRNA have been identified (9, 18).MicroRNAs are an intriguing class of small noncoding RNA molecules which, in mammals, regulate gene expression primarily by imperfect base pairing with the

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“…Advanced research has shown that miRNAs are actively involved in the regeneration, regulation, and function of the central nervous system (88,89). Studies in C. elegans and cultured cell systems have shown that several distinct miRNAs are actively linked to neurodegenerative diseases, such as Parkinson's and Alzheimer's disease (90). Experimental data from AD patients' brains has shown downregulation of miR 29ab-1 and miR-107 (91,92).…”

Section: Microrna In Neurological Disordersmentioning

confidence: 99%

Pygmy MicroRNA: Surveillance Cops in Therapy Kingdom

Bhadra

Patra

Chhatai

et al. 2016

Mol Med

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MicroRNAs (miRNAs) are well preserved in every animal. These pygmy-sized (21-23 nt) noncoding RNAs scattered in the genome are responsible for micromanaging versatile gene regulation. There is involvement of miRNAs as surveillance cops in all human diseases including cardiovascular defects, tumor formation, reproductive pathways, and neurological and autoimmune disorders. The effective functional role of miRNA can be reduced by chemical entities of antisense oligonucleotides and versatile small molecules that support the views of novel therapies of different human diseases. In this study, we have updated our current understanding of designing and synthesizing miRNA-controlled therapeutic chemicals. We have also proposed various in vivo delivery strategies and discuss their ongoing challenges to combat incorporation hurdles in live cells and animals. Lastly, we have demonstrated the current progress of miRNA modulation in the treatment of human diseases to provide an alternative approach to gene therapy.

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Searching for MIND: MicroRNAs in Neurodegenerative Diseases

Cited by 42 publications

References 43 publications

Deregulation of microRNAs by HIV-1 Vpr Protein Leads to the Development of Neurocognitive Disorders

Deregulation of microRNAs by HIV-1 Vpr Protein Leads to the Development of Neurocognitive Disorders

MicroRNA-101 Regulates Amyloid Precursor Protein Expression in Hippocampal Neurons

Pygmy MicroRNA: Surveillance Cops in Therapy Kingdom

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