subject: Role of Micro RNA in Neuro-degenerative diseases [print this page] Introduction:- Introduction:-
Neurodegenerative diseases result from dysfunction, progressive deterioration, and extensive loss of neurons in the central and/or peripheral nervous system. In this regard, Alzheimer's disease (AD), Parkinson's disease (PD), prion disease, amyotrophic lateral sclerosis (ALS), and hereditary spastic paraplegia may have a genetic or sporadic etiology. Instead, Huntington's disease (HD) and metabolic disorders with neurological involvement, such as the GM2-gangliosidosescan only be genetically transmitted. There is now compelling evidence that disregulation of miRNA networks is implicated in the development and onset of human neurodegenerative diseases. This, in turn, may provide the opportunity to elucidate underlying disease mechanisms and open up novel strategies for therapeutic applications.
Alzheimer's Disease (AD) :-
AD is the most common form of dementia. While several hypotheses have been proposed to explain the disease's etiology, the causes of AD and means of stopping its progression are still elusive matters. Features of the disease encompass neuronal loss, intraneuronal neurofibrillary tangles (i.e., aggregates of the microtubule-associated protein tau following hyper-phosphorylation), and extracellular deposits of amyloid plaques (i.e., deposits of A-peptide). Only 10%15% of AD cases represent an inheritable disease which follows an autosomal dominant Mendelian pattern, while the majority arises sporadically. Apparently, the disease may be caused by a genetic predisposition, as shown by the identification of specific DNA mutations in a large number of families. Despite a variable etiology, a common pathogenetic cascade resulting from distinct gene defects and/or unknown environmental factors cannot be ruled out. For example, accumulation of the A peptide, the cause of which is unknown, is consistently observed. In approximately 30% of sporadic AD patient samples, the expression of BACE1 protein, a secretase associated with the formation of A-peptide, is significantly increased. In AD, several miRNAs exhibit abnormal expression levels, suggesting a dysfunctional orchestration of gene expression. Interestingly, Boissonneault et al. have recently found that miR-298 and miR-328 bind to the 3'-UTR of BACE1 mRNA, thereby producing a regulatory effect on enzyme expression in cultured neuronal (N2a) cells. Presence of both miR-298 and miR-328 in the hippocampus of APPSwe/PS1 mice, a well-documented model for AD, and the observation that their levels of expression decrease with aging suggest that altered levels of these miRNAs may deregulate BACE1 and, in turn, lead to increased A formation and disease progression. Finally, a recent work from Carrettiero et al. shows that miR-128a regulates the cochaperone BAG2 and, in turn, a pathway of degradation for microtubule-associated tauproteins with a propensity for misfolding. BAG2 would normally direct tau toward an ubiquitin-independent pathway and selectively reduce the levels of sarkosyl-insoluble protein. Thus, the observation that miR-128a is upregulated in AD may highlight a molecular mechanism that underlies tau inclusions in neurodegeneration. Taken together, these findings suggest a mechanistic involvement of miRNAs in both the amyloid and tau hypotheses for AD pathogenesis.
Parkinson's Disease (PD) :-
PD is the second most common neurodegenerative disorder, characterized by resting tremor, muscular rigidity, bradykinesia, and impaired balance and coordination. Other symptoms include dysautonomia, dystonic cramps, and dementia. Typical pathological features are loss of dopaminergic neurons in the substantia nigra (SN) and presence of Lewy bodies, which consist of intracellular inclusions affecting surviving neurons in various areas of the brain. Several gene loci have been implicated in autosomal, dominant forms of PD. These include PARK1 and PARK4 (due to a mutation or a triplication of the -synuclein gene [SNCA] on 4q21 and 4p15, resp.), PARK3 on 2p13, PARK5 (due to a mutation in the UCHL1 gene) on 4p14, PARK8 (due to a mutation in the LRRK2 gene) on 12q12, PARK10 on 1p, PARK11 on 2q, and PARK13 (due to a mutation in the HTRA2 gene) on 2p12The implication of miRNAs in PD is intriguing. In murine models, the competence of embryonic stem cells to differentiate into midbrain dopamine neurons in vitro was shown to be disrupted by Dicer deletion and subsequent suppression of miRNA biogenesis, suggesting a physiological role for miRNAs in cell differentiation and/or survival. These results were confirmed in vivo, using mice conditional for Dicer, which exhibited impaired locomotor activity that recapitulated motility problems observed in PD patients.Through a subtractive approach, performed by comparing miRNA expression profiles in normal human adult versus PD patients midbrains, it was shown that miR-133b is specifically missing in PD and that, based on both over-expression and inhibitory tests in vitro, is likely implicated in the maturation and function of dopaminergic neurons. A markedly reduced expression of miR-133b was found in Aphakia mice, a dopaminergic neuron deficiency model, which lack Pitx3, a homeobox transcription factor required for neuron survival and normal motor activity susceptible to polymorphisms associated with sporadic PD. Together, these observations suggest a relationship between miR-133b and Pitx3, which operate through a negative feedback loop, wherein Pitx3 promotes the expression of miR-133b that, in turn, downregulates Pitx3. While these results point to a functional role of the miR-133b/Pitx3 system in ensuring correct dopaminergic function, miR-133b knock-out mice, which are currently unavailable, would establish the extent of miR-133b impact on PD etiology. On the other hand, a more recent study showed that deletion of Dicer in dopaminoceptive neurons of the murine striatum led to aberrant anatomical features (smaller brain, reduced neuron size, astrogliosis) and motor impairments (clasping and ataxia) but, surprisingly, not neurodegeneration. As dysfunction, but not necessarily loss, of dopaminoceptive neurons was previously implicated in PD, these observations, taken together, suggest that the link between Dicer, miRNAs, and neurodegeneration is restricted to dopaminergic neurons, thereby pointing to distinct functional roles in dopaminoceptive cells. Finally, Wang et al. found that in PD brains and in vitro cell models disruption of the binding site for miRNA- 433 led to increased translation of fibroblast growth factor- 20 (FGF20). Notably, an FGF20 polymorphism at 8p21.322 was previously identified as a PD risk factor correlated with increased -synuclein expression, and consequently PD onset.
Huntington's Disease (HD:-
HD is a fatal, neurodegenerative disorder characterized by involuntary ballistic movements, depression, and dementia. Hallmarks of HD are progressive chorea, rigidity, and frequent accurrence of seizures, emotional problems, loss of cognition, as well as atrophy of the caudate nucleus. The causal factor of HD is a gene mutation consisting of abnormally extended repeats of the CAG sequence within the HTT gene, which translates into a huntingtin protein containing an excessively increased glutamine segment. Disruption of miRNA homeostasis, most likely in connection with an aberrant functionality of the transcriptional repressor REST, was recently shown to play a dynamic role in HD. In fact, levels of several miRNAs with upstream RE1 sites are decreased in HD patient cortices relative to healthy controls. Interestingly, one of these, the bifunctional, brain enriched miR-9/miR-9targets two components of the REST complex: miR-9 targets REST and miR-9 targets CoREST. As a consequence of a markedly altered miRNA expression, target mRNAs are subject to dysregulated levels which, in turn, affect the physiological status of forebrain neuron.
miRNAs and Tumours of the Nervous System :-
Several studies found that a high proportion of genomic loci containing miRNA genes exhibit DNA copy number alterations in common cancersand miRNA mis-expression has also been described in tumours of the nervous system and. miRNAs have been shown to act either as tumor suppressors or oncogenes and, depending on the mRNA target, may accelerate the oncogenic process. A suppressor effect was observed in pituitary adenomas, the most common tumors of the central nervous system, in which down-regulation of miR-15a and miR-16 correlates with tumor size. Other miRNAs, such as the miR-155 and miR17-92 cluster, have an oncogenic effect. The consequence of an upregulation of miR-21 has been characterized in glioblastoma tumor cells, wherein the knockdown of miR-21 led to increased apoptotic cell death, suggesting that this miRNA may act as an antiapoptotic player. In addition, miRNA profiling in glioblastoma cells has shown high levels of miR-221, miR-128, miR-181a, and miR-181b and low levels of miR-181c.miRNA expression analysis may also be used for medulloblastoma prognosis. Down-regulation of miR-9 and miR-125a was observed in aggressive brain malignancy, which results in the activation of medulloblastoma cell growth and arrest of apoptosis by activation of the pro-proliferative truncated TrkC isoform.Based on these findings, the potential to modulate multiple messages at the same time via miRNA technology would therefore represent an intriguing prospect for cancer treatment.
