ReviewMicroRNAs and deregulated gene expression networks in neurodegeneration
Introduction
The main characteristic of neurodegeneration is the progressive dysfunction, deterioration and eventual loss of neurons in the nervous system. This can be caused by a variety of factors such as the intrinsic properties of the underlying neurodegenerative disorder, ischemia, inflammation, and toxic insult (Bossy-Wetzel et al., 2004, Jellinger, 2009). A pathological hallmark of many neurodegenerative diseases is a disturbed cellular homeostasis with accumulation of misfolded proteins in the form of cellular aggregates and the cytotoxicity of intermediate products, such as oligomers and protofibrils. Many of the mechanisms in neuronal cell function in physiology and pathophysiology are currently not well understood and the impact of neurodegeneration on patients is often devastating, since there are no or only insufficient therapies available.
Neurodegenerative diseases can be roughly classified in two forms: The familial (early onset) forms that are associated with genetic mutations, such as the poly glutamine (polyQ) disorders (Ataxia and Huntington's disease - HD), and some forms of Parkinson disease (PD), and the sporadic (late onset) forms, for which in many cases the cause is not known, e.g., sporadic Alzheimer's disease (AD), amyotrophic lateral sclerosis (ALS), and sporadic PD. Despite this distinction, there is also mounting evidence that sporadic neurodegeneration is a combination of genetic predisposition and environmental factors with overlapping disease mechanisms as seen in the familial disease forms (a comprehensive review on the genetic and biochemical classifications of neurodegenerative disease was recently published by (Jellinger, 2009)).
Although the understanding of the pathophysiology of neurodegeneration is still limited, research has progressed over the past years and, in particular, the development of new technologies has offered new insights into the molecular properties of the degenerating neuronal cell. Also, new discoveries have changed some of our understanding of disease mechanisms and this includes miRNAs, which introduce an entirely novel level of regulatory control over gene expression (Ambros, 2004). This new concept seems to be an important part in a diversity of cell systems in development, function and disease. In the nervous system, miRNAs are essential in developmental timing, cell proliferation, cell death and patterning as well as function and identity of neural cell populations (Ambros, 2004, Barbato et al., 2008, Fiore et al., 2008, Kuss and Chen, 2008, Satterlee et al., 2007, Schratt, 2009). In addition, there is also mounting evidence that miRNAs might play a role in neurodegeneration (Barbato et al., 2009, Bushati and Cohen, 2008, Eacker et al., 2009, Hebert and De Strooper, 2009, Hebert et al., 2009, Nelson et al., 2008, Singh, 2007). However, in contrast to an increasingly vast amount of knowledge about miRNA function in developmental systems and some disease entities such as, e.g., cancer (Croce, 2009, Garzon et al., 2009, Krichevsky and Gabriely, 2009), there is to date very little information of how miRNAs function in the pathogenesis of neurodegenerative diseases. This is in part due to the difficulties of evaluating miRNAs in patient populations - which represents a general caveat in studying neurodegeneration. Because of an often very subtle symptomatology at disease onset, the slow disease progression and long duration as well as the restricted accessibility of nerve cells, the availability of patients-derived neural tissue is limited. On the other hand, it is possible to study miRNAs in experimental in vitro and in vivo model systems for neurodegenerative diseases, and some of them have already served to generate new information about potential functions of these molecules in disease mechanisms (e.g., Junn et al., 2009, Schaefer et al., 2007, Wang et al., 2009). However, results from these studies tend to be limited to isolated disease aspects often leading to correlative conclusions that yet have to be confirmed in the complex biological systems of patients.
Concepts of miRNA function in neurodegenerative diseases have been extensively discussed (Barbato et al., 2009, Bushati and Cohen, 2008, Eacker et al., 2009, Hebert and De Strooper, 2007, Hebert and De Strooper, 2009, Nelson et al., 2008, Singh, 2007) and are based on information from miRNA function in other systems as well as on a few studies demonstrating experimental evidence of the potential role of miRNAs in pathogenetic mechanisms of neurodegeneration. In this review we will focus on the molecular properties based on data from gene expression profiles of patients-derived brain cells affected with neurodegenerative diseases and discuss how deregulated expression networks could be associated with miRNAs. In addition, we will extend our discussion to the view that the function of miRNAs in normal and abnormal regulatory networks might be common between neurons and other cell systems and how this view could influence the general understanding of pathogenetic mechanisms in neurodegeneration.
Section snippets
Gene expression profiling and general concepts of mechanisms in neurodegeneration
The combined feature of neurodegenerative diseases is the progressive degeneration, function, and loss of neuronal cells. However, despite this commonality, there are also clear differences as there is distinctive and localized neuronal cell loss in the brain. Neurodegeneration appears to be “cell-specific” predominantly affecting entorhinal and neocortical glutamatergic and nucleus basalis cholinergic neurons in AD, nigrostriatal neurons in PD, Purkinje cells in Spinocerebellar Ataxia (SCA),
miRNAs in neurodegeneration
As discussed above, large-scale gene profiling has revealed new insights into the molecular properties of disease-affected neurons and an increasing body of data now offers the opportunity to tie together different aspects of normal and abnormal cell function, i.e., the influence of genetic predisposition (variability in coding and non-coding sequences), levels of gene expression, functionality of gene products (pre- and post-translation), gender, and the role of regulatory mechanisms, such as
Regulatory miRNA/mRNA expression networks to develop new conceptual views of neurodegeneration
A key question in understanding the role of miRNAs in neurodegeneration is how to link their function to regulatory gene expression networks in neurons. There are three different parameters to being considered: a role of miRNAs in defining the pan-neuronal phenotype and in fine-tuning neuronal subtypes, a “common” role of miRNAs in neuronal cellular homeostasis, and a “specific” role of miRNAs in distinct neuronal cell function (Fig. 2). This miRNA paradigm is closely linked to the gene
Concluding remarks
In the past decade, it has become clear that miRNAs are essential key molecules in neuronal cell development, identity, and function. Moreover, there is increasing evidence that miRNAs also seem to play a role in neurodegeneration. However, this conceptual view is still in the early phases of being fundamentally substantiated by experimental data or patient-relevant studies that delineate the functions of miRNAs in the complex systems of neurodegenerative disorders. Advances in understanding
Acknowledgments
This research was in part supported by a grant from the Massachusetts’ Alzheimer's Disease Research Center and the Harvard NeuroDiscovery Center and NIH/NINDS NS067335. The author wants to thank Filip Simunovic and Dr. Wilson Woo for critically reading the manuscript.
References (83)
- et al.
MicroRNA-124a regulates Foxa2 expression and intracellular signaling in pancreatic beta-cell lines
J. Biol. Chem.
(2007) MicroRNAs: genomics, biogenesis, mechanism, and function
Cell
(2004)- et al.
Relief of microRNA-mediated translational repression in human cells subjected to stress
Cell
(2006) - et al.
MicroRNA-298 and microRNA-328 regulate expression of mouse beta-amyloid precursor protein-converting enzyme 1
J. Biol. Chem.
(2009) - et al.
MicroRNAs in neurodegeneration
Curr. Opin. Neurobiol.
(2008) - et al.
Effects of gender on nigral gene expression and parkinson disease
Neurobiol. Dis.
(2007) - et al.
microRNA modulation of circadian-clock period and entrainment
Neuron
(2007) - et al.
MicroRNA function in neuronal development, plasticity and disease
Biochim. Biophys. Acta
(2008) - et al.
Alterations of the microRNA network cause neurodegenerative disease
Trends Neurosci.
(2009) - et al.
MicroRNA regulation of Alzheimer's amyloid precursor protein expression
Neurobiol. Dis.
(2009)
Differential allelic expression of dopamine D1 receptor gene (DRD1) is modulated by microRNA miR-504
Biol. Psychiatry
Foxa1 and Foxa2 function both upstream of and cooperatively with Lmx1a and Lmx1b in a feedforward loop promoting mesodiencephalic dopaminergic neuron development
Dev. Biol.
Gene expression profiles derived from single cells in human postmortem brain
Brain Res. Brain Res. Protoc.
Induction of specific micro RNA (miRNA) species by ROS-generating metal sulfates in primary human brain cells
J. Inorg. Biochem.
The MicroRNA miR-124 promotes neuronal differentiation by triggering brain-specific alternative pre-mRNA splicing
Mol. Cell
Neuronal gene expression profiling: uncovering the molecular biology of neurodegenerative disease
Prog. Brain Res.
Organization of the human embryonic ventral mesencephalon
Gene Expr. Patterns
In situ hybridization is a necessary experimental complement to microRNA (miRNA) expression profiling in the human brain
Neurosci. Lett.
Fine-tuning neural gene expression with microRNAs
Curr. Opin. Neurobiol.
Variation in the miRNA-433 binding site of FGF20 confers risk for Parkinson disease by overexpression of alpha-synuclein
Am. J. Hum. Genet.
miR-34a, a microRNA up-regulated in a double transgenic mouse model of Alzheimer's disease, inhibits bcl2 translation
Brain Res. Bull.
Genetic control of human brain transcript expression in Alzheimer disease
Am. J. Hum. Genet.
Target identification for CNS diseases by transcriptional profiling
Neuropsychopharmacology
The functions of animal microRNAs
Nature
Foxa1 and Foxa2 transcription factors regulate differentiation of midbrain dopaminergic neurons
Adv. Exp. Med. Biol.
MicroRNA-338 regulates local cytochrome c oxidase IV mRNA levels and oxidative phosphorylation in the axons of sympathetic neurons
J. Neurosci.
Thinking about RNA? MicroRNAs in the brain
Mamm. Genome
Searching for MIND: microRNAs in neurodegenerative diseases
J. Biomed. Biotechnol.
The pathogenic mechanisms of polyglutamine diseases and current therapeutic strategies
J. Neurochem.
Stress-induced reversal of microRNA repression and mRNA P-body localization in human cells
Cold Spring Harb. Symp. Quant. Biol.
RNA editing of human microRNAs
Genome Biol.
Molecular pathways to neurodegeneration
Nat. Med.
Comprehensive mRNA expression profiling distinguishes tauopathies and identifies shared molecular pathways
PLoS ONE
A functional study of miR-124 in the developing neural tube
Genes Dev.
miR-124 regulates adult neurogenesis in the subventricular zone stem cell niche
Nat. Neurosci.
Identification of miRNA changes in Alzheimer's disease brain and CSF yields putative biomarkers and insights into disease pathways
J. Alzheimers Dis.
Causes and consequences of microRNA dysregulation in cancer
Nat. Rev. Genet.
miRNAs are essential for survival and differentiation of newborn neurons but not for expansion of neural progenitors during early neurogenesis in the mouse embryonic neocortex
Development
Genetics of motor neuron disorders: new insights into pathogenic mechanisms
Nat. Rev. Genet.
Understanding microRNAs in neurodegeneration
Nat. Rev. Neurosci.
Mef2-mediated transcription of the miR379-410 cluster regulates activity-dependent dendritogenesis by fine-tuning Pumilio2 protein levels
Embo J.
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