Intracellular organelle deficits driving Alzheimer's disease
Intracellular organelle deficits driving Alzheimer's disease
批准号:
10058739
负责人:
Israel Sekler
金额:
$171.76万
依托单位国家:
美国
项目类别:
财政年份:
2020
资助国家:
美国
项目状态:
已结题
起止时间:
2020-09-01 至 2024-08-31
关键词:
Abeta clearanceAffectAlzheimer&aposs DiseaseAlzheimer&aposs disease pathologyAlzheimer&aposs disease patientAmyloidAmyloid beta-42AttenuatedAutomobile DrivingAutophagocytosisAutophagosomeBiochemicalBioenergeticsBuffersCalciumCalcium SignalingCell modelCellsClinical TrialsConfocal MicroscopyCoupledCouplingDefectDevelopmentDiseaseDisease ProgressionDyesElectrophysiology (science)ElementsEndoplasmic ReticulumExcisionFeedbackFibroblastsFunctional disorderGene ExpressionGoalsHealthHistopathologyHomeostasisHumanITPR1 geneImageImmunoassayImpaired cognitionImpairmentInositolLeadLinkLysosome ProtonLysosomesMeasuresMediatingMembrane PotentialsMemory impairmentMitochondriaMusNeurodegenerative DisordersNeurofibrillary TanglesNeuronsOrganellesOutcomeOutputOxidative StressPathogenesisPathogenicityPathologyPathway interactionsPeriodicityPost-Translational Protein ProcessingProcessProteinsProteolysisPublic HealthRNA SplicingRegulationResolutionResourcesRestRoleRyanodine Receptor Calcium Release ChannelSignal TransductionSiteSourceStructureSynapsesSynaptic TransmissionTestingTherapeuticTranscriptional Activationabeta accumulationalkalinityamyloid peptideamyloid structurecellular pathologycognitive functionfluorescence imaginghyperphosphorylated taumisfolded proteinmitochondrial dysfunctionmitochondrial membranemouse modelmutantneuron lossnovel therapeuticsoperationprotein aggregationresponserestorationtau Proteinstau aggregationtherapeutic targettranscription factortreatment strategytripolyphosphatetwo photon microscopy
中文摘要
阿尔茨海默病(AD)是一种以β-淀粉样蛋白聚集为特征的破坏性神经退行性疾病
英文摘要
Alzheimer’s disease (AD) is a devastating neurodegenerative disorder characterized by aggregation of β-amyloid
(Aβ) peptides, neurofibrillary tangles composed of hyperphosphorylated tau, and a progressive loss of cognitive
function. While much is known regarding the biochemical composition and structure of amyloid and tau in AD,
relatively less focus has been placed on the intracellular handling of detrimental protein products, and more
specifically, how upstream deficits in organelle function can accelerate the disease process and directly
contribute to memory impairments. While neurons rely on dedicated organelles to execute specific functions and
sustain health, several in particular have been linked to AD pathophysiology, including the ER, which is important
for protein assembly and intracellular calcium signaling; lysosomes, which are critical for breaking down and
removing the cellular debris and misfolded proteins collected by authophagosomes; and mitochondria, which are
responsible for the bioenergetics of the cell (Mustaly et al., 2018). In the global operations of maintaining
neuronal viability, the functions of these organelles are highly inter-dependent, and they are often physically
coupled to one another. Despite the close coupling, their respective roles in contributing to AD have typically
been studied in isolation. For example, there are compelling studies detailing aspects of ER, lysosome, or
mitochondrial dysfunction in AD, yet substantially less is understood about how altered interactions among these
organelles can lead to pathogenic cascades. This isolationist approach may lead to critical oversights in
understanding key processes in AD and missing potential therapeutic opportunities. Thus, the overall goal of
this study is to identify mechanisms underlying deficiencies in specific organelle functions and examine how this
affects their interactions, characterize how this potentiates AD pathology, and establish the upstream drivers of
this cascade for consideration as a therapeutic target. This will be accomplished through the following Aims: Aim
I: Determine if the AD-associated disruption in ER function disrupts lysosomal dynamics and clearance of
aggregated proteins. Aim II: Determine the mechanism by which excess ER-Ca2+ release disrupts mitochondrial
function and degradation. Aim III: Establish upstream drivers of intracellular pathogenic cascades and determine
if targeting ER-homeostasis will resolve lysosomal and mitochondrial defects. The proposed study will have a
significant impact on the field as it will provide new mechanistic information about how misaggregated proteins
accumulate in AD and are associated with altered ER signaling. Moreover, targeting specific intracellular
organelles may reveal effective new treatment strategies for AD.
期刊论文(6)
专著(0)
科研奖励(0)
会议论文
DOI:
10.1073/pnas.2211999119
发表时间:
2022-12-06
期刊:
Proceedings of the National Academy of Sciences of the United States of America
影响因子:
11.1
作者:
[]
通讯作者:
海外基金