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Establishing RNA Binding Proteins as...

Maziuk, Brandon F.

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Establishing RNA Binding Proteins as Key Components of Alzheimer'S Disease Pathophysiology.

紀錄類型:	書目-電子資源 : Monograph/item
正題名/作者:	Establishing RNA Binding Proteins as Key Components of Alzheimer'S Disease Pathophysiology./
作者:	Maziuk, Brandon F.
出版者:	Ann Arbor : ProQuest Dissertations & Theses, : 2020,
面頁冊數:	160 p.
附註:	Source: Dissertations Abstracts International, Volume: 81-09, Section: B.
Contained By:	Dissertations Abstracts International81-09B.
標題:	Pharmacology. -
電子資源:	http://pqdd.sinica.edu.tw/twdaoapp/servlet/advanced?query=27665891
ISBN:	9781392731550

Establishing RNA Binding Proteins as Key Components of Alzheimer'S Disease Pathophysiology.
Maziuk, Brandon F.

Establishing RNA Binding Proteins as Key Components of Alzheimer'S Disease Pathophysiology. - Ann Arbor : ProQuest Dissertations & Theses, 2020 - 160 p.

Source: Dissertations Abstracts International, Volume: 81-09, Section: B.

Thesis (Ph.D.)--Boston University, 2020.

This item must not be sold to any third party vendors.

Aggregation of the microtubule associated protein tau (MAPT) into filamentous neurofibrillary tangles (NFTs) is a defining molecular hallmark of neurodegenerative diseases such as Alzheimer's disease (AD) and frontotemporal dementia (FTD). Despite the discovery of NFTs decades ago, the molecular mechanisms underpinning their formation and neurotoxicity have remained elusive. Recently, our lab has shown that stress granule (SG) associated RNA binding proteins (RBPs) co-deposit with pathological tau in mouse models and human disease; reduction of the SG associated protein TIA1 also protects against tau-mediated behavioral deficits and degeneration. Here we demonstrate that RBPs facilitate tau pathogenesis and exhibit prominent signs of dysfunction early in disease. By immunoprecipitating pathological tau from the transgenic rTg4510 AD mouse model, we have found that tau associates with many RBPs and ribosomal subunits, and these associations change as tau pathology develops. These RBPs also become increasingly insoluble in tauopathy, consistent with the formation of fibrillar aggregates. We also show by immunohistochemistry that as tau forms mature neurofibrillary tangles, RBPs lose their interaction with tau and aggregate to the periphery of the tangle in mouse and human tissue, suggesting that RBPs contribute to earlier stages of tau aggregation. Seeing this, we sought to determine at what point of tau pathogenesis RBPs become relevant to the disease process. Using the PS19 mouse line, which develops tangle pathology more slowly than the rTg4510, we have found that RBP immunohistochemistry is highly sensitive to tissue fixation methods, that different brain regions have unique localization patterns of canonically nuclear RBPs, and that transgenic tau mice show striking changes in hippocampal RBP regulation very early in tau pathogenesis. This precedes an eventual destabilization and disruption of the nuclear lamina. We further show that overexpression of TIA1 accelerates the somatodendritic accumulation of phosphorylated tau in vivo, and that TIA1 granules co-localize with granules of misfolded tau. Together these findings support the idea that ribonucleoprotein granules contribute significantly to early pathological tau formation and that misregulation of these proteins progresses in tandem with tau pathology. RBPs thus offer promising new therapeutic targets for Alzheimer's disease and related tauopathies.

ISBN: 9781392731550Subjects--Topical Terms:

634543
Pharmacology.
Subjects--Index Terms:

Alzheimer's

Establishing RNA Binding Proteins as Key Components of Alzheimer'S Disease Pathophysiology.
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520 $a Aggregation of the microtubule associated protein tau (MAPT) into filamentous neurofibrillary tangles (NFTs) is a defining molecular hallmark of neurodegenerative diseases such as Alzheimer's disease (AD) and frontotemporal dementia (FTD). Despite the discovery of NFTs decades ago, the molecular mechanisms underpinning their formation and neurotoxicity have remained elusive. Recently, our lab has shown that stress granule (SG) associated RNA binding proteins (RBPs) co-deposit with pathological tau in mouse models and human disease; reduction of the SG associated protein TIA1 also protects against tau-mediated behavioral deficits and degeneration. Here we demonstrate that RBPs facilitate tau pathogenesis and exhibit prominent signs of dysfunction early in disease. By immunoprecipitating pathological tau from the transgenic rTg4510 AD mouse model, we have found that tau associates with many RBPs and ribosomal subunits, and these associations change as tau pathology develops. These RBPs also become increasingly insoluble in tauopathy, consistent with the formation of fibrillar aggregates. We also show by immunohistochemistry that as tau forms mature neurofibrillary tangles, RBPs lose their interaction with tau and aggregate to the periphery of the tangle in mouse and human tissue, suggesting that RBPs contribute to earlier stages of tau aggregation. Seeing this, we sought to determine at what point of tau pathogenesis RBPs become relevant to the disease process. Using the PS19 mouse line, which develops tangle pathology more slowly than the rTg4510, we have found that RBP immunohistochemistry is highly sensitive to tissue fixation methods, that different brain regions have unique localization patterns of canonically nuclear RBPs, and that transgenic tau mice show striking changes in hippocampal RBP regulation very early in tau pathogenesis. This precedes an eventual destabilization and disruption of the nuclear lamina. We further show that overexpression of TIA1 accelerates the somatodendritic accumulation of phosphorylated tau in vivo, and that TIA1 granules co-localize with granules of misfolded tau. Together these findings support the idea that ribonucleoprotein granules contribute significantly to early pathological tau formation and that misregulation of these proteins progresses in tandem with tau pathology. RBPs thus offer promising new therapeutic targets for Alzheimer's disease and related tauopathies.
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