Abstract：
:We have analyzed the impact of Parkinson's disease (PD)-related genetic variants on splicing using dedicated minigene assays. Out of 14 putative splicing variants in 5 genes (PINK1, [PTEN induced kinase 1]; LRPPRC, [leucine-rich pentatricopeptide repeat containing protein]; TFAM, [mitochondrial transcription factor A]; PARK2, [parkin RBR E3 ubiquitin protein ligase]; and HSPA9, [heat shock protein family A (Hsp70) member 9]), 4 LRPPRC variants, (IVS32-3C>T, IVS35+14C>T, IVS35+15C>T, and IVS9+30A>G) influenced, pre-messenger RNA splicing by modulating the inclusion of the respective exons. In addition, 1-Methyl-4-phenylpyridinium ion-induced splicing changes of endogenous LRPPRC messenger RNA, reproduced the effect of the LRPPRC IVS35+14C>T mutation. Using silencing and overexpression methods, we show that LRPPRC exon 33 splicing is negatively regulated by heterogeneous nuclear ribonucleoprotein A1 both in a minigene and endogenous context. Furthermore, exon 33 exclusion due to PD-associated mutation IVS32-3C>T or heterogeneous nuclear ribonucleoprotein A1 overexpression and exon 35 exclusion due to IVS35+14C>T can be rescued by co-expression of modified U1 small nuclear RNAs, providing a potentially useful therapeutic strategy. Our results indicate for the first time that LRPPRC intronic variants can affect normal splicing of this gene and may influence disease risk in PD and related disorders.
journal_name
Neurobiol Agingjournal_title
Neurobiology of agingauthors
Gaweda-Walerych K,Mohagheghi F,Zekanowski C,Buratti Edoi
10.1016/j.neurobiolaging.2016.07.014subject
Has Abstractpub_date
2016-11-01 00:00:00pages
127-138eissn
0197-4580issn
1558-1497pii
S0197-4580(16)30151-8journal_volume
47pub_type
杂志文章abstract：:The objective of this study was to examine the distribution and severity of tau-PET binding in cognitively normal adults with preclinical Alzheimer's disease as determined by positive beta-amyloid PET. 18F-AV-1451 tau-PET data from 109 cognitively normal older adults were processed with 34 cortical and 9 subcortical F...
journal_title：Neurobiology of aging
pub_type： 杂志文章
doi：10.1016/j.neurobiolaging.2018.08.022
更新日期：2018-12-01 00:00:00
abstract：:Amyloid beta (Aβ) peptide, the main component of senile plaques in patients with Alzheimer's disease (AD), is derived from proteolytic cleavage of amyloid precursor protein (APP) by β- and γ-secretases. Alpha-cleavage of APP by α-secretase has a potential to preclude the generation of Aβ because it occurs within the A...
journal_title：Neurobiology of aging
pub_type： 杂志文章
doi：10.1016/j.neurobiolaging.2013.07.014
更新日期：2014-01-01 00:00:00
abstract：:The fine structural organization of the floor of the third cerebral ventricle (dorsum of the median eminence of the hypothalamus) of 2 normal adult mice Fisher 344 rats was compared and contrasted with that of 2 aged rats 30 months old. Closely juxtaposed tanycytes (specialized ependymal cells) of normal young adults ...
journal_title：Neurobiology of aging
pub_type： 杂志文章
doi：10.1016/0197-4580(81)90004-x
更新日期：1981-07-01 00:00:00
abstract：:The G4C2 hexanucleotide repeat expansion, located in the first intron of the C9ORF72 gene, represents a major genetic hallmark of amyotrophic lateral sclerosis and frontotemporal lobar degeneration. Several hypotheses have been proposed on how the transcribed repeat RNA leads to the development of amyotrophic lateral ...
journal_title：Neurobiology of aging
pub_type： 杂志文章
doi：10.1016/j.neurobiolaging.2014.09.012
更新日期：2015-02-01 00:00:00
abstract：:The H1 MAPT haplotype in the 17q21 chromosomal region has been associated with several neurodegenerative diseases. Some reports have suggested that there is an association between genetic variants within the H1 haplotype with Parkinson's disease (PD), progressive supranuclear palsy (PSP) and corticobasal degeneration ...
journal_title：Neurobiology of aging
pub_type： 杂志文章
doi：10.1016/j.neurobiolaging.2009.09.011
更新日期：2011-03-01 00:00:00
abstract：:Elevated expression of human hyperphosphorylated tau is associated with neuronal loss and white matter (WM) pathology in Alzheimer's disease (AD) and related neurodegenerative disorders. Using in vivo diffusion tensor magnetic resonance imaging (DT-MRI) at 11.1 Tesla we measured age-related alterations in WM diffusion...
journal_title：Neurobiology of aging
pub_type： 杂志文章
doi：10.1016/j.neurobiolaging.2013.12.009
更新日期：2014-06-01 00:00:00
abstract：:Several genes and risk factors are associated with Parkinson's disease (PD). Although many of the genetic markers belong to a common pathway, a unifying pathogenetic mechanism is yet to be found. Also, missing heritability analyses have estimated that only part of the genetic influence contributing to PD has been foun...
journal_title：Neurobiology of aging
pub_type： 杂志文章
doi：10.1016/j.neurobiolaging.2017.01.019
更新日期：2017-05-01 00:00:00
abstract：:The low density lipoprotein receptor (LDLR) is an attractive candidate gene for genetic association with Alzheimer's disease (AD) because: (i) the LDLR is an apolipoprotein E (apoE) receptor, alleles of which have been associated with AD, (ii) LDLR resides at chromosome 19p13.3 within a region linked to AD, and (iii) ...
journal_title：Neurobiology of aging
pub_type： 杂志文章
doi：10.1016/j.neurobiolaging.2004.09.001
更新日期：2005-01-01 00:00:00
abstract：:Increasing evidence suggests that cholesterol plays a central role in the pathophysiology of Alzheimer's disease (AD). Caveolin is a cholesterol-binding membrane protein involved in cellular cholesterol transport. We investigated the changes in the protein amount of hippocampal caveolin of autopsy-confirmed AD and age...
journal_title：Neurobiology of aging
pub_type： 杂志文章
doi：10.1016/j.neurobiolaging.2003.07.004
更新日期：2004-07-01 00:00:00
abstract：:Glial cell line-derived neurotrophic factor (GDNF) supports the viability of midbrain dopamine (DA) neurons that degenerate in Parkinson's disease. Middle-aged, 12 month old, Gdnf heterozygous (Gdnf(+/-)) mice have diminished spontaneous locomotor activity and enhanced synaptosomal DA uptake compared with wild type mi...
journal_title：Neurobiology of aging
pub_type： 杂志文章
doi：10.1016/j.neurobiolaging.2010.10.013
更新日期：2012-02-01 00:00:00
abstract：:The effects of age, subcortical vascular disease, apolipoprotein E (APOE) epsilon4 allele and hypertension on entorhinal cortex (ERC) and hippocampal atrophy rates were explored in a longitudinal MRI study with 42 cognitively normal (CN) elderly subjects from 58 to 87 years old. The volumes of the ERC, hippocampus, an...
journal_title：Neurobiology of aging
pub_type： 杂志文章
doi：10.1016/j.neurobiolaging.2005.03.021
更新日期：2006-05-01 00:00:00
abstract：:Temperature regulation was evaluated in senescent (34-40 month old) and adult (8-9 month old) female Iva:WIWU and Emd:Wi-AF/Han rats. Injection of 1.5 mg/kg BW apomorphine HCl or 1.0 mg/kg BW oxotremorine sesquifumarate produced comparable maximal hypothermic responses in adult and senescent rats. However, the latency...
journal_title：Neurobiology of aging
pub_type： 杂志文章
doi：10.1016/0197-4580(85)90029-6
更新日期：1985-07-01 00:00:00
abstract：:Long-term dietary supplementation with resveratrol protects against cardiovascular disease, osteoporesis, and metabolic decline. This study determined how long-term dietary resveratrol treatment protects against retinal ganglion cell (RGC) dendrite loss after optic nerve injury and alters the resolution of the unfolde...
journal_title：Neurobiology of aging
pub_type： 杂志文章
doi：10.1016/j.neurobiolaging.2014.12.021
更新日期：2015-05-01 00:00:00
abstract：:The activity of beta-secretase (BACE1), the endo-protease essential for the production of amyloid beta (Abeta) peptides, is increased in brain of late-onset sporadic Alzheimer's disease (AD), and oxidative stress is the potential cause of this event. Oxidative stress up-regulates the expression and the activity of BAC...
journal_title：Neurobiology of aging
pub_type： 杂志文章
doi：10.1016/j.neurobiolaging.2007.12.015
更新日期：2009-10-01 00:00:00
abstract：:Aging is associated with alterations in different systems that govern neuronal calcium homeostasis. This study was designed to determine whether any of these alterations may contribute to the decline in spatial working memory that is observed in old rats. Several parameters [initial (5 s) and steady state (15 min) 45C...
journal_title：Neurobiology of aging
pub_type： 杂志文章
doi：10.1016/0197-4580(93)90106-l
更新日期：1993-09-01 00:00:00
abstract：:Aging has been related to diminished cognitive function, which could be a result of ineffective synaptic function. We have previously shown that synaptic plasma membrane proteins supporting synaptic integrity and neurotransmission were downregulated in docosahexaenoic acid (DHA)-deprived brains, suggesting an importan...
journal_title：Neurobiology of aging
pub_type： 杂志文章
doi：10.1016/j.neurobiolaging.2016.02.007
更新日期：2016-05-01 00:00:00
abstract：:Amyotrophic lateral sclerosis (ALS) is a devastating neurodegenerative disorder characterized by an extensive loss of motor neurons in the primary motor cortex, brainstem, and spinal cord. Genetic studies report a high heritability of ALS. Recently, whole-exome sequencing analysis of familial ALS (FALS) patients allow...
journal_title：Neurobiology of aging
pub_type： 杂志文章
doi：10.1016/j.neurobiolaging.2015.09.013
更新日期：2016-01-01 00:00:00
abstract：:Decreased levels of cerebrospinal fluid (CSF) Abeta42 is a diagnostic marker of Alzheimer's disease. To clarify the biological basis of this marker, the physiological alterations of CSF Abeta40 and Abeta42 by aging were studied. CSF samples from 92 normal subjects between 8 and 89 years old were measured using a speci...
journal_title：Neurobiology of aging
pub_type： 杂志文章
doi：10.1016/s0197-4580(00)00229-3
更新日期：2001-03-01 00:00:00
abstract：:Brain injury increases the risk of Alzheimer's disease (AD) through unknown mechanisms. We studied deposition of amyloid-beta protein (Abeta) in cells exposed to transforming growth factor beta1 (TGFbeta1), a cytokine that regulates cell metabolism during brain injury, and apolipoproteinE (apoE), the major lipid trans...
journal_title：Neurobiology of aging
pub_type： 杂志文章
doi：10.1016/s0197-4580(02)00095-7
更新日期：2003-03-01 00:00:00
abstract：:To investigate whether dramatically waned dentate neurogenesis during aging is linked to diminution in neural stem/progenitor cell (NSC) number, we counted cells immunopositive for Sox-2 (a putative marker of NSCs) in the subgranular zone (SGZ) of young, middle-aged and aged F344 rats. The young SGZ comprised approxim...
journal_title：Neurobiology of aging
pub_type： 杂志文章
doi：10.1016/j.neurobiolaging.2006.09.015
更新日期：2008-01-01 00:00:00
abstract：:Elevated serum and cerebrospinal fluid concentrations of S100β, a protein predominantly found in glia, are associated with intracranial injury and neurodegeneration, although concentrations are also influenced by several other factors. The longitudinal association between serum S100β concentrations and brain health in...
journal_title：Neurobiology of aging
pub_type： 杂志文章
doi：10.1016/j.neurobiolaging.2018.05.029
更新日期：2018-09-01 00:00:00
abstract：:Relationships between age-related changes in sleep patterns and neuronal activity have received scant attention. In the present study, reticularis pontis oralis (RPO) and ventral tegmental nucleus of Gudden (VTN) neurons were recorded in unanesthetized restrained young (3 months) and old (23 months) Sprague-Dawley rat...
journal_title：Neurobiology of aging
pub_type： 杂志文章
doi：10.1016/s0197-4580(01)00339-6
更新日期：2002-07-01 00:00:00
abstract：:Alzheimer's disease (AD) is a genetically complex disorder for which the definite diagnosis is only accomplished postmortem. Mutations in 3 genes (APP, PSEN1, and PSEN2) are known to cause AD, but a large number of familial cases do not harbor mutations in these genes and several unidentified genes that contain diseas...
journal_title：Neurobiology of aging
pub_type： 杂志文章
doi：10.1016/j.neurobiolaging.2011.10.009
更新日期：2012-05-01 00:00:00
abstract：:Cortico-striatal-thalamic network functional connectivity (FC) and its relationship with levodopa (L-dopa) were investigated in 69 patients with hemiparkinsonism (25 drug-naïve [n-PD] and 44 under stable/optimized dopaminergic treatment [t-PD]) and 27 controls. Relative to controls, n-PD patients showed an increased F...
journal_title：Neurobiology of aging
pub_type： 杂志文章
doi：10.1016/j.neurobiolaging.2014.05.032
更新日期：2014-11-01 00:00:00
abstract：:Aged rats perform poorly on spatial learning tasks, a cognitive impairment which has been linked to the failure of hippocampal networks to fully encode changes in the external environment [Barnes CA, Suster MS, Shen J, McNaughton BL. Multistability of cognitive maps in the hippocampus of old rats. Nature 1997;388(6639...
journal_title：Neurobiology of aging
pub_type： 杂志文章
doi：10.1016/j.neurobiolaging.2004.09.006
更新日期：2005-07-01 00:00:00
abstract：:Exercise has emerged as a powerful variable that can improve cognitive function and delay age-associated cognitive decline and Alzheimer's disease (AD); however, the underlying mechanisms are poorly understood. To determine if protective mechanisms may occur at the transcriptional level, we used microarrays to investi...
journal_title：Neurobiology of aging
pub_type： 杂志文章
doi：10.1016/j.neurobiolaging.2019.02.012
更新日期：2019-06-01 00:00:00
abstract：:We previously found a selective loss of the brain specific APP-695 transcript in Alzheimer's disease (AD) cortex, which results in a 2.5-fold increase in the APP-751/APP-695 transcript ratio in AD (9). Here we report a similar increase in APP-751/APP-695 mRNA ratio in AD hippocampus. However, the cerebellum had a 6-fo...
journal_title：Neurobiology of aging
pub_type： 更正并重新发布的文章,杂志文章
doi：10.1016/0197-4580(89)90017-1
更新日期：1989-11-01 00:00:00
abstract：:Data are emerging that the altered development of adrenocortical and emotional reactivity in individuals exposed perinatally to adverse events is reflected in cognitive change and that maternal care is an important determinant. However, early trauma does not cause a generalized cognitive decline at older age, but rath...
journal_title：Neurobiology of aging
pub_type： 评论,杂志文章,评审
doi：10.1016/s0197-4580(03)00057-5
更新日期：2003-05-01 00:00:00
abstract：:In Alzheimer's disease (AD), amyloid-β (Aβ) deposits accumulate in the brain parenchyma and contain fibrils of aggregated heterogeneous Aβ peptides. In addition to fibrils, Aβ aggregates into stable soluble species (termed Aβ oligomers), which are increasingly viewed as the key drivers of early neurodegenerative event...
journal_title：Neurobiology of aging
pub_type： 杂志文章
doi：10.1016/j.neurobiolaging.2014.05.023
更新日期：2014-11-01 00:00:00
abstract：:In this review the relationship between the basal forebrain cholinergic system and memory is explored. It appears that different components of the cholinergic forebrain system [e.g., medial septum (MS) and nucleus basalis magnocellularis (NBM)] have dissociable mnemonic functions in animals, and comparable mnemonic fu...
journal_title：Neurobiology of aging
pub_type： 杂志文章,评审
doi：10.1016/s0197-4580(88)80122-2
更新日期：1988-09-01 00:00:00
