Abstract:
:Charcot-Marie-Tooth disease (CMT) is a genetic disorder that can be caused by aberrations in >80 genes. CMT has heterogeneous modes of inheritance, including autosomal dominant, autosomal recessive, X-linked dominant, and X-linked recessive. Over 95% of cases are dominantly inherited. In this study, we investigated whether regulation of a mutant allele by an allele-specific small interfering RNA (siRNA) can alleviate the demyelinating neuropathic phenotype of CMT. We designed 19 different allele-specific siRNAs for Trembler J (Tr-J) mice harboring a naturally occurring mutation (Leu16Pro) in Pmp22. Using a luciferase assay, we identified an siRNA that specifically and selectively reduced the expression level of the mutant allele and reversed the low viability of Schwann cells caused by mutant Pmp22 over-expression in vitro. The in vivo efficacy of the allele-specific siRNA was assessed by its intraperitoneal injection to postnatal day 6 of Tr-J mice. Administration of the allele-specific siRNA to Tr-J mice significantly enhanced motor function and muscle volume, as assessed by the rotarod test and magnetic resonance imaging analysis, respectively. Increases in motor nerve conduction velocity and compound muscle action potentials were also observed in the treated mice. In addition, myelination, as evidenced by toluidine blue staining and electron microscopy, was augmented in the sciatic nerves of the mice after allele-specific siRNA treatment. After validating suppression of the Pmp22 mutant allele at the mRNA level in the Schwann cells of Tr-J mice, we observed increased expression levels of myelinating proteins such as myelin basic protein and myelin protein zero. These data indicate that selective suppression of the Pmp22 mutant allele by non-viral delivery of siRNA alleviates the demyelinating neuropathic phenotypes of CMT in vivo, implicating allele-specific siRNA treatment as a potent therapeutic strategy for dominantly inherited peripheral neuropathies.
journal_name
Neurobiol Disjournal_title
Neurobiology of diseaseauthors
Lee JS,Chang EH,Koo OJ,Jwa DH,Mo WM,Kwak G,Moon HW,Park HT,Hong YB,Choi BOdoi
10.1016/j.nbd.2017.01.006subject
Has Abstractpub_date
2017-04-01 00:00:00pages
99-107eissn
0969-9961issn
1095-953Xpii
S0969-9961(17)30015-3journal_volume
100pub_type
杂志文章abstract::Food restriction has been widely associated with beneficial effects on brain aging and age-related neurodegenerative diseases such as Alzheimer's disease. However, previous studies on the effects of food restriction on aging- or pathology-related cognitive decline are controversial, emphasizing the importance of the t...
journal_title:Neurobiology of disease
pub_type: 杂志文章
doi:10.1016/j.nbd.2020.104745
更新日期:2020-03-01 00:00:00
abstract::It has been proposed that Alzheimer disease (AD) is associated with a "disconnection syndrome" due to the gradual loss of morphological and functional integrity of cortico-cortical pathways. This hypothesis derives from indirect neuropathological observations, but definitive evidence that AD primarily targets cortico-...
journal_title:Neurobiology of disease
pub_type: 杂志文章
doi:10.1016/j.nbd.2004.01.008
更新日期:2004-06-01 00:00:00
abstract::Astrocytes are abundant neuron-supporting glial cells that harbor a powerful arsenal of neuroprotective antioxidative molecules and neurotrophic factors. Here we examined whether enrichment with healthy striatal astrocytes can provide neuroprotection against progressive dopaminergic neurodegeneration. Serotonin 1A (5-...
journal_title:Neurobiology of disease
pub_type: 杂志文章
doi:10.1016/j.nbd.2013.08.003
更新日期:2013-11-01 00:00:00
abstract::The molecular mechanisms of major mental illnesses, such as schizophrenia and bipolar disorder, are unclear. To address this fundamental question, many groups have studied molecular expression profiles in postmortem brains and other tissues from patients compared with those from normal controls. Development of unbiase...
journal_title:Neurobiology of disease
pub_type: 杂志文章,评审
doi:10.1016/j.nbd.2011.08.025
更新日期:2012-01-01 00:00:00
abstract::The spreading of pathology through neuronal pathways is likely to be the cause of the progressive cognitive loss observed in Alzheimer's disease (AD) and other neurodegenerative diseases. We have recently shown the propagation of AD pathology via cell-to-cell transfer of oligomeric amyloid beta (Aβ) residues 1-42 (oAβ...
journal_title:Neurobiology of disease
pub_type: 杂志文章
doi:10.1016/j.nbd.2013.12.019
更新日期:2014-05-01 00:00:00
abstract::The brain of Alzheimer's disease patients shows abundant dystrophic neurites in close proximity to fibrillar beta-amyloid (A beta) plaques, and activated glial cells. We evaluated the influence of pro-inflammatory molecules (LPS + IFN-gamma) on A beta(1-42) neurotoxicity. 2 microM A beta(1-42) induced apoptosis of hip...
journal_title:Neurobiology of disease
pub_type: 杂志文章
doi:10.1016/j.nbd.2005.01.007
更新日期:2005-06-01 00:00:00
abstract::Human genetics provides unbiased insights into the causes of human disease, which can be used to create a foundation for effective ways to more accurately diagnose patients, stratify patients for more successful clinical trials, discover and develop new therapies, and ultimately help patients choose the safest and mos...
journal_title:Neurobiology of disease
pub_type: 杂志文章,评审
doi:10.1016/j.nbd.2020.105088
更新日期:2020-12-01 00:00:00
abstract::Huntington's disease (HD) is a genetic neurodegenerative disease characterized by movement disorders, cognitive decline and neuropsychiatric symptoms. HD is caused by expanded CAG tract within the coding region of Huntingtin protein. Despite major insights into the molecular mechanisms leading to HD, no effective cure...
journal_title:Neurobiology of disease
pub_type: 杂志文章
doi:10.1016/j.nbd.2012.04.007
更新日期:2012-08-01 00:00:00
abstract::Environmental toxicants and, in particular, pesticides have been implicated as risk factors in Parkinson's disease (PD). The purpose of this study was to determine if selective nigrostriatal degeneration could be reproduced by systemic exposure of mice to the widely used herbicide paraquat. Repeated intraperitoneal pa...
journal_title:Neurobiology of disease
pub_type: 杂志文章
doi:10.1006/nbdi.2002.0507
更新日期:2002-07-01 00:00:00
abstract::Approximately 10% of amyotrophic lateral sclerosis (ALS) cases are familial (FALS), and approximately 25% of FALS cases are caused by mutations in superoxide dismutase-1 (SOD1). Mutant (MT) SOD1 kills motor neurons because of the mutant protein's toxicity; however, the basis for toxicity is unknown. We electroporated ...
journal_title:Neurobiology of disease
pub_type: 杂志文章
doi:10.1016/j.nbd.2005.07.006
更新日期:2006-01-01 00:00:00
abstract::Attention deficit hyperactivity disorder (ADHD) is characterized by hyperactivity, inattention, and impulsivity. The coloboma mouse model of ADHD exhibits profound hyperactivity. To determine whether coloboma mice exhibit other signs of ADHD, we assessed latent inhibition as a test of attention, and impulsivity in a d...
journal_title:Neurobiology of disease
pub_type: 杂志文章
doi:10.1016/j.nbd.2006.09.009
更新日期:2007-01-01 00:00:00
abstract::Recently, we showed that oxidative stress activates the expression and activity of the beta-site AbetaPP-cleaving enzyme (BACE), an aspartyl protease responsible for the beta-secretase cleavage of AbetaPP. The identification of compounds able to prevent the induction of this event is an important goal of therapeutic s...
journal_title:Neurobiology of disease
pub_type: 杂志文章
doi:10.1016/s0969-9961(03)00131-1
更新日期:2003-11-01 00:00:00
abstract::Based on in vitro studies, it is hypothesized that neurotrophic factor deprivation following deafferentation elicits an oxidative state change in the deafferented neuron and the formation of free radicals that then signal cell death pathways. This pathway to cell death was tested in vivo by assessing the efficacy of a...
journal_title:Neurobiology of disease
pub_type: 杂志文章
doi:10.1016/j.nbd.2006.09.012
更新日期:2007-02-01 00:00:00
abstract::Hereditary sensory neuropathy type 1 (HSN-1) is a peripheral neuropathy most frequently caused by mutations in the SPTLC1 or SPTLC2 genes, which code for two subunits of the enzyme serine palmitoyltransferase (SPT). SPT catalyzes the first step of de novo sphingolipid synthesis. Mutations in SPT result in a change in ...
journal_title:Neurobiology of disease
pub_type: 杂志文章
doi:10.1016/j.nbd.2018.05.008
更新日期:2018-09-01 00:00:00
abstract::We determined whether tetrahydrobiopterin(BH4), an endogenous cofactor for dopamine(DA) synthesis, causes preferential damage to DArgic neurons among primary cultured rat mesencephalic neurons and whether the death mechanism has relevance to Parkinson's disease (PD). DArgic neurons were more vulnerable to BH4 than non...
journal_title:Neurobiology of disease
pub_type: 杂志文章
doi:10.1016/j.nbd.2006.08.024
更新日期:2007-01-01 00:00:00
abstract::Amyloid deposition appears to be an early and crucial event in Alzheimer's disease (AD). To generate animal models of AD, mice expressing full-length amyloid precursor protein (APP), with mutations linked to FAD, have been created. These animals exhibit abnormalities characteristic of AD, including deposits of beta-am...
journal_title:Neurobiology of disease
pub_type: 杂志文章
doi:10.1016/s0969-9961(02)00012-8
更新日期:2003-04-01 00:00:00
abstract::Symptoms in Parkinson's Disease (PD) have been linked to oscillatory activity within the basal ganglia. In humans, such activity has been detected mainly in the local field potentials (LFPs) recorded from electrode contacts used for deep brain stimulation. Although most studies have focused on activity within the subt...
journal_title:Neurobiology of disease
pub_type: 杂志文章
doi:10.1016/j.nbd.2013.01.020
更新日期:2013-06-01 00:00:00
abstract:BACKGROUND/INTRODUCTION:The neuroinflammatory response plays a major role in the secondary injury cascade after traumatic spinal cord injury (SCI). To date, systemic anti-inflammatory medications such as methylprednisolone sodium succinate (MPSS) have shown promise in SCI. However, systemic immunosuppression can have d...
journal_title:Neurobiology of disease
pub_type: 杂志文章
doi:10.1016/j.nbd.2020.105187
更新日期:2021-01-01 00:00:00
abstract::The worldwide proliferation of mobile phones raises the question of the effects of 900-MHz electromagnetic fields (EMF) on the brain. Using a head-only exposure device in the rat, we showed that a 15-min exposure to 900-MHz pulsed microwaves at a high brain-averaged power of 6 W/kg induced a strong glial reaction in t...
journal_title:Neurobiology of disease
pub_type: 杂志文章
doi:10.1016/j.nbd.2004.07.004
更新日期:2004-12-01 00:00:00
abstract::Males and females show a different predisposition to certain types of seizures in clinical studies. Animal studies have provided growing evidence for sexual dimorphism of certain brain regions, including those that control seizures. Seizures are modulated by networks involving subcortical structures, including thalamu...
journal_title:Neurobiology of disease
pub_type: 杂志文章,评审
doi:10.1016/j.nbd.2014.05.010
更新日期:2014-12-01 00:00:00
abstract::Excitotoxicity plays a central role in the neuronal damage during ischemic stroke. Although growing evidence suggests that activation of extrasynaptic NMDA receptors initiates neuronal death, no direct evidence demonstrated their activation during ischemia. Using rat hippocampal slices, we detected oxygen-glucose depr...
journal_title:Neurobiology of disease
pub_type: 杂志文章
doi:10.1016/j.nbd.2013.05.005
更新日期:2013-10-01 00:00:00
abstract::Since aberrant miRNA expression has been implicated in numerous brain diseases, we studied miRNA expression and miRNA regulation of important signaling pathways during temporal lobe epileptogenesis in order to identify possible targets for epilepsy therapy. The temporal profile of miRNA expression was analyzed in thre...
journal_title:Neurobiology of disease
pub_type: 杂志文章
doi:10.1016/j.nbd.2013.10.026
更新日期:2014-02-01 00:00:00
abstract::Although there are no proven ways to delay onset or slow progression of Alzheimer's disease (AD), studies suggest that diet can affect risk. Pomegranates contain very high levels of antioxidant polyphenolic substances as compared to other fruits and vegetables. Polyphenols have been shown to be neuroprotective in diff...
journal_title:Neurobiology of disease
pub_type: 杂志文章
doi:10.1016/j.nbd.2006.08.006
更新日期:2006-12-01 00:00:00
abstract::Tamoxifen (TAM) is a selective estrogen receptor modulator, widely used in the treatment and prevention of estrogen-dependent breast cancer. Although with great clinical results, women on TAM therapy still report several side effects, such as sexual dysfunction, which impairs quality of life. The anatomo-functional su...
journal_title:Neurobiology of disease
pub_type: 杂志文章
doi:10.1016/j.nbd.2017.09.009
更新日期:2018-01-01 00:00:00
abstract::Human apolipoprotein E (apoE) exists in three isoforms: apoE2, apoE3 and apoE4. APOE ε4 is a major genetic risk factor for cardiovascular disease (CVD) and Alzheimer's disease (AD). ApoE mediates cholesterol metabolism by binding various receptors. The low-density lipoprotein receptor (LDLR) has a high affinity for ap...
journal_title:Neurobiology of disease
pub_type: 杂志文章
doi:10.1016/j.nbd.2013.12.016
更新日期:2014-04-01 00:00:00
abstract::Ethanol-induced damage in the developing hippocampus may result in cognitive deficits such as those observed in fetal alcohol spectrum disorder (FASD). Cognitive deficits in FASD are partially mediated by alterations in glutamatergic synaptic transmission. Recently, we reported that synaptic transmission mediated by a...
journal_title:Neurobiology of disease
pub_type: 杂志文章
doi:10.1016/j.nbd.2007.08.001
更新日期:2008-01-01 00:00:00
abstract::Voltage-gated sodium channels (VGSCs) are essential for the generation and propagation of action potentials in electrically excitable cells. Dominant mutations in SCN1A, which encodes the Nav1.1 VGSC α-subunit, underlie several forms of epilepsy, including Dravet syndrome (DS) and genetic epilepsy with febrile seizure...
journal_title:Neurobiology of disease
pub_type: 杂志文章
doi:10.1016/j.nbd.2012.08.012
更新日期:2013-01-01 00:00:00
abstract::Amyotrophic lateral sclerosis (ALS) is characterized by a progressive loss of large motor neurons in the brain and spinal cord. Amyloid precursor protein (APP), the transmembrane precursor of beta-amyloid (A beta), accumulates in the anterior horn motor neurons of ALS patients with mild lesions. APP undergoes an alter...
journal_title:Neurobiology of disease
pub_type: 杂志文章
doi:10.1016/j.nbd.2005.01.012
更新日期:2005-06-01 00:00:00
abstract::Depression affects at least 322 million people globally, or approximately 4.4% of the world's population. While the earnestness of researchers and clinicians to understand and treat depression is not waning, the number of individuals suffering from depression continues to increase over and above the rate of global pop...
journal_title:Neurobiology of disease
pub_type: 杂志文章,评审
doi:10.1016/j.nbd.2019.104578
更新日期:2020-02-01 00:00:00
abstract::Oxidative stress and protein aggregation are biochemical hallmarks of Parkinson's disease (PD), a frequent sporadic late-onset degenerative disorder particularly of dopaminergic neurons in the substantia nigra, resulting in impaired spontaneous movement. PARK6 is a rare autosomal-recessively inherited disorder, mimick...
journal_title:Neurobiology of disease
pub_type: 杂志文章
doi:10.1016/j.nbd.2006.10.007
更新日期:2007-02-01 00:00:00