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 most promising therapeutic option based on their risk profile. But the process for translating basic observations from human genetics studies into pathogenic disease mechanisms and treatments is laborious and complex, and this challenge has particularly slowed the development of interventions for neurodegenerative disease. In this review, we discuss the many steps in the process, the important considerations at each stage, and some of the latest tools and technologies that are available to help investigators translate insights from human genetics into diagnostic and therapeutic strategies that will lead to the sort of advances in clinical care that make a difference for patients.
journal_name
Neurobiol Disjournal_title
Neurobiology of diseaseauthors
Finkbeiner Sdoi
10.1016/j.nbd.2020.105088subject
Has Abstractpub_date
2020-12-01 00:00:00pages
105088eissn
0969-9961issn
1095-953Xpii
S0969-9961(20)30363-6journal_volume
146pub_type
杂志文章,评审abstract：:Huntington's disease (HD) is an autosomal dominant neurodegenerative disorder characterized behaviorally by chorea, incoordination, and shortened lifespan and neuropathologically by huntingtin inclusions and neuronal degeneration. In order to facilitate studies of pathogenesis and therapeutics, we have generated a new...
journal_title：Neurobiology of disease
pub_type： 杂志文章
doi：10.1016/j.nbd.2005.07.014
更新日期：2006-02-01 00:00:00
abstract：:Long-term consequences of status epilepticus (SE) occur in a significant proportion of those who survive the acute episode. We developed an in vivo model of acute focal neocortical SE (FSE) to study long-term effects on local cortical structure and function and potential strategies to mitigate adverse consequences of ...
journal_title：Neurobiology of disease
pub_type： 杂志文章
doi：10.1016/j.nbd.2020.104949
更新日期：2020-08-01 00:00:00
abstract：:Midlife cognitive decline is now recognized as a factor of poor prognosis for late-life dementia. Although an epidemiological link has been suggested with high fat diet (HFD)-induced metabolic disorders, the effect of a long period of HFD on midlife cerebrovascular and cognitive functions remains unproven. A cohort of...
journal_title：Neurobiology of disease
pub_type： 杂志文章,评审
doi：10.1016/j.nbd.2019.104536
更新日期：2019-10-01 00:00:00
abstract：:Huntington's disease (HD) is a lethal, neurodegenerative disorder caused by expansion of the polyglutamine repeat in the Huntingtin gene (HTT), leading to mutant protein misfolding, aggregation, and neuronal death. Feeding a Drosophila HD model cystamine, or expressing a transgene encoding the anti-htt intracellular a...
journal_title：Neurobiology of disease
pub_type： 杂志文章
doi：10.1016/j.nbd.2010.04.007
更新日期：2010-10-01 00:00:00
abstract：:Premature stop codons in CACNA1A, which encodes the alpha(1A) subunit of neuronal P/Q-type (Ca(V)2.1) Ca(2+) channels, cause episodic ataxia type 2 (EA2). CACNA1A undergoes extensive alternative splicing, which contributes to the pharmacological and kinetic heterogeneity of Ca(V)2.1-mediated Ca(2+) currents. We identi...
journal_title：Neurobiology of disease
pub_type： 杂志文章
doi：10.1016/j.nbd.2008.06.002
更新日期：2008-10-01 00:00:00
abstract：:Biallelic nonsense mutations of SYNE1 underlie a variable array of cerebellar and non-cerebellar pathologies of unknown molecular etiology. SYNE1 encodes multiple isoforms of Nesprin1 that associate with the nuclear envelope, with large cerebellar synapses and with ciliary rootlets of photoreceptors. Using two novel m...
journal_title：Neurobiology of disease
pub_type： 杂志文章
doi：10.1016/j.nbd.2018.04.006
更新日期：2018-07-01 00:00:00
abstract：:Deletion of the mTOR pathway inhibitor PTEN from postnatally-generated hippocampal dentate granule cells causes epilepsy. Here, we conducted field potential, whole cell recording and single cell morphology studies to begin to elucidate the mechanisms by which granule cell-specific PTEN-loss produces disease. Cells fro...
journal_title：Neurobiology of disease
pub_type： 杂志文章
doi：10.1016/j.nbd.2017.08.014
更新日期：2017-12-01 00:00:00
abstract：:Brain glucose supplies most of the carbon required for acetyl-coenzyme A (acetyl-CoA) generation (an important step for myelin synthesis) and for neurotransmitter production via further metabolism of acetyl-CoA in the tricarboxylic acid (TCA) cycle. However, it is not known whether reduced brain glucose transporter ty...
journal_title：Neurobiology of disease
pub_type： 杂志文章
doi：10.1016/j.nbd.2012.04.011
更新日期：2012-10-01 00:00:00
abstract：:Developing in vivo functional and structural neuroimaging assays in Dyt1 ΔGAG heterozygous knock-in (Dyt1 KI) mice provide insight into the pathophysiology underlying DYT1 dystonia. In the current study, we examined in vivo functional connectivity of large-scale cortical and subcortical networks in Dyt1 KI mice and wi...
journal_title：Neurobiology of disease
pub_type： 杂志文章
doi：10.1016/j.nbd.2016.07.005
更新日期：2016-11-01 00:00:00
abstract：:Mitochondrial dysfunction plays an important role in the pathogenesis of neurodegenerative diseases, numerous other disease states and senescence. The ability to monitor reactive oxygen species (ROS) within tissues and over time in animal model systems is of significant research value. Recently, redox-sensitive fluore...
journal_title：Neurobiology of disease
pub_type： 杂志文章
doi：10.1016/j.nbd.2011.08.022
更新日期：2012-01-01 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：:In this study, we tested whether over-expressing the GABA(B) receptor R1a subtype in transgenic mouse forebrain neurons would be sufficient to induce spontaneous absence seizures. As hypothesized, these transgenic mice develop spontaneous, recurrent, bilaterally synchronous, 3-6 Hz slow spike and wave discharges betwe...
journal_title：Neurobiology of disease
pub_type： 杂志文章
doi：10.1016/j.nbd.2007.01.013
更新日期：2007-05-01 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：:Uridine, like adenosine, is released under sustained depolarization and it can inhibit hippocampal neuronal activity, suggesting that uridine may be released during seizures and can be involved in epileptic mechanisms. In an in vivo microdialysis study, we measured the extracellular changes of nucleoside and amino aci...
journal_title：Neurobiology of disease
pub_type： 杂志文章
doi：10.1016/j.nbd.2004.02.011
更新日期：2004-08-01 00:00:00
abstract：:Early exposure to general anesthesia (GA) causes developmental neuroapoptosis in the mammalian brain and long-term cognitive impairment. Recent evidence suggests that GA also causes functional and morphological impairment of the immature neuronal mitochondria. Injured mitochondria could be a significant source of reac...
journal_title：Neurobiology of disease
pub_type： 杂志文章
doi：10.1016/j.nbd.2011.12.022
更新日期：2012-03-01 00:00:00
abstract：:Huntington disease (HD) is a fatal neurodegenerative disorder caused by an expanded CAG repeat. Its length can be used to estimate the time of clinical diagnosis, which is defined by overt motor symptoms. Non-motor symptoms begin before motor onset, and involve changes in hypothalamus-regulated functions such as sleep...
journal_title：Neurobiology of disease
pub_type： 杂志文章,多中心研究
doi：10.1016/j.nbd.2010.07.013
更新日期：2010-12-01 00:00:00
abstract：:Age-inappropriate expression of juvenile NMDA receptors (NMDARs) containing GluN3A subunits has been linked to synapse loss and death of spiny projection neurons of the striatum (SPNs) in Huntington's disease (HD). Here we show that suppressing GluN3A expression prevents a multivariate synaptic transmission phenotype ...
journal_title：Neurobiology of disease
pub_type： 杂志文章
doi：10.1016/j.nbd.2016.04.001
更新日期：2016-09-01 00:00:00
abstract：:Insulin deficiency may contribute toward the neurological deficits of diabetic polyneuropathy (DPN). In particular, the unique trophic properties of insulin, acting on sensory neuron and axon receptors offer an approach toward reversing loss of skin axons that develops during diabetes. Here we examined how local cutan...
journal_title：Neurobiology of disease
pub_type： 杂志文章
doi：10.1016/j.nbd.2011.04.012
更新日期：2011-08-01 00:00:00
abstract：:The repertoire of biochemicals (or small molecules) present in cells, tissue, and body fluids is known as the metabolome. Today, clinicians utilize only a very small part of the information contained in the metabolome, as revealed by the quantification of a limited set of analytes to gain information on human health. ...
journal_title：Neurobiology of disease
pub_type： 杂志文章,评审
doi：10.1016/j.nbd.2009.02.019
更新日期：2009-08-01 00:00:00
abstract：:Neuropathological findings in the amygdala obtained from patients with mesial temporal lobe epilepsy (MTLE) indicate varying degrees of histopathological alterations, such as neuronal loss and gliosis. The mechanisms underlying cellular damage in the amygdala of patients with MTLE have not been fully elucidated. In th...
journal_title：Neurobiology of disease
pub_type： 杂志文章
doi：10.1016/j.nbd.2018.12.017
更新日期：2019-04-01 00:00:00
abstract：:Transgenic mice expressing mutant human amyloid precursor protein (APP) develop an age-dependent amyloid pathology and memory deficits, but no overt neuronal loss. Here, in mice overexpressing wild-type human APP (hAPP(wt)) we found an early memory impairment, particularly in the water maze and to a lesser extent in t...
journal_title：Neurobiology of disease
pub_type： 杂志文章
doi：10.1016/j.nbd.2008.11.005
更新日期：2009-03-01 00:00:00
abstract：:Cerebral autosomal dominant arteriopathy with subcortical infarct and leukoencephalopathy (CADASIL) is a cerebral small vascular disease caused by NOTCH3 gene mutation in vascular smooth muscle cells (VSMCs), leading to ischemic stroke and vascular dementia. To date, the pathogenesis of CADASIL remains poorly understo...
journal_title：Neurobiology of disease
pub_type： 杂志文章
doi：10.1016/j.nbd.2019.104561
更新日期：2019-12-01 00:00:00
abstract：:Neurodegenerative diseases encompass a large group of neurological disorders. Clinical symptoms can include memory loss, cognitive impairment, loss of movement or loss of control of movement, and loss of sensation. Symptoms are typically adult onset (although severe cases can occur in adolescents) and are reflective o...
journal_title：Neurobiology of disease
pub_type： 杂志文章,评审
doi：10.1016/j.nbd.2010.05.026
更新日期：2010-10-01 00:00:00
abstract：:It is well known that the uncoupling between local cerebral glucose utilization (LCGU) and local cerebral blood flow (LCBF), i.e. decrease in LCBF rates with high LCGU, is frequently associated with seizure-induced neuronal damage. This study was performed to assess if the neuroprotective effect of the adenosinergic A...
journal_title：Neurobiology of disease
pub_type： 杂志文章
doi：10.1016/j.nbd.2010.09.004
更新日期：2011-01-01 00:00:00
abstract：:The developing rodent brain is vulnerable to pharmacological blockade of N-methyl-d-aspartate (NMDA) receptors which can lead to severe and disseminated apoptotic neurodegeneration. Here, we show that systemic administration of the NMDA receptor antagonist MK801 to 7-day-old rats leads to impaired activity of extracel...
journal_title：Neurobiology of disease
pub_type： 杂志文章
doi：10.1016/j.nbd.2004.03.013
更新日期：2004-07-01 00:00:00
abstract：:The interest in the pedunculopontine tegmental nucleus (PPTg), a structure located in the brainstem at the level of the pontomesencephalic junction, has greatly increased in recent years because it is involved in the regulation of physiological functions that fail in Parkinson's disease and because it is a promising t...
journal_title：Neurobiology of disease
pub_type： 杂志文章,评审
doi：10.1016/j.nbd.2018.03.004
更新日期：2019-08-01 00:00:00
abstract：:In this review, we describe insights into beta-amyloid (Abeta) production using aged dogs as a model of human brain aging. The advantage of using dogs is that they naturally accumulate Abeta neuropathology with age. In parallel, dogs also develop age-associated learning and memory impairments. Thus, dogs can complemen...
journal_title：Neurobiology of disease
pub_type： 杂志文章,评审
doi：10.1006/nbdi.2002.0476
更新日期：2002-02-01 00:00:00
abstract：:The rapidly emerging science of epigenetics and epigenomic medicine promises to reveal novel insights into the susceptibility to and the onset and progression of epileptic disorders. Epigenetic regulatory mechanisms are now implicated in orchestrating aspects of neural development (e.g., cell fate specification and ma...
journal_title：Neurobiology of disease
pub_type： 杂志文章,评审
doi：10.1016/j.nbd.2010.02.005
更新日期：2010-07-01 00:00:00
abstract：:Familial amyotrophic lateral sclerosis (FALS) has been modeled in transgenic mice by introducing mutated versions of human genomic DNA encompassing the entire gene for Cu,Zn superoxide dismutase (SOD1). In this setting, the transgene is expressed throughout the body and results in mice that faithfully recapitulate man...
journal_title：Neurobiology of disease
pub_type： 杂志文章
doi：10.1016/j.nbd.2005.06.005
更新日期：2005-12-01 00:00:00
abstract：:The blossoming field of epitranscriptomics has recently garnered attention across many fields by findings that chemical modifications on RNA have immense biological consequences. Methylation of nucleotides in RNA, including N6-methyladenosine (m6A), 2-O-dimethyladenosine (m6Am), N1-methyladenosine (m1A), 5-methylcytos...
journal_title：Neurobiology of disease
pub_type： 杂志文章,评审
doi：10.1016/j.nbd.2020.105139
更新日期：2020-12-01 00:00:00
