Modulators of Tauopathy in the Rtg4510 Mouse Model

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Material Information

Title:
Modulators of Tauopathy in the Rtg4510 Mouse Model
Physical Description:
1 online resource (178 p.)
Language:
english
Creator:
Bailey, Rachel M
Publisher:
University of Florida
Place of Publication:
Gainesville, Fla.
Publication Date:

Thesis/Dissertation Information

Degree:
Doctorate ( Ph.D.)
Degree Grantor:
University of Florida
Degree Disciplines:
Medical Sciences, Neuroscience (IDP)
Committee Chair:
LEWIS,JADA M
Committee Co-Chair:
GIASSON,BENOIT IVAN
Committee Members:
BIZON,JENNIFER L
BORCHELT,DAVID R
LEWIN,ALFRED S

Subjects

Subjects / Keywords:
disease -- lrrk2 -- model -- mouse -- neurodegeneration -- parkinson's -- tau -- tauopathy
Neuroscience (IDP) -- Dissertations, Academic -- UF
Genre:
Medical Sciences thesis, Ph.D.
bibliography   ( marcgt )
theses   ( marcgt )
government publication (state, provincial, terriorial, dependent)   ( marcgt )
born-digital   ( sobekcm )
Electronic Thesis or Dissertation

Notes

Abstract:
Tauopathies are neurodegenerative disorders characterized by the accumulation of intracellular neurofibrillary tangles composed of abnormally phosphorylated tau.  Tau bind sand stabilizes microtubules, a function thought to be disrupted by atypical hyperphosphorylation associated with increased aggregation; yet it is not fully understood how tau dysfunction contributes to disease.  Identification of factors that modify the progression of tauopathy is critical to elucidate mechanisms of tau pathogenesis and for disease intervention.  The focus of this dissertation is to identify and characterize modulators of tauopathy using the rTg4510 mouse model.  Recapitulating human tauopathy, rTg4510 mice have progressive cognitive decline, increased insoluble tau, robust taupathology and age-dependent neurodegeneration. One of the most common strain backgrounds in mouse modeling is C57BL/6and it has been reported that this strain background alters the tauopathy phenotype of a second mouse model.  To determine if the phenotype of rTg4510 mice was similarly affected, we comparedrTg4510 mice on the original background to rTg4510 mice containing a C57BL/6background.  Overall, our data show that introduction of the C57BL/6 strain into the rTg4510 mouse background modestly alters the tau phosphorylation reported in rTg4510 on the original background, an effect that coincides with increased murine tau phosphorylation.  In contrast, behavioral and neurodegenerative outcomes were not altered.  These studies suggest that the C57BL/6 background does not inherently protect against tauopathy. Mutations in the gene encoding leucine-rich repeat kinase 2 (LRRK2) are the most frequent cause of familial Parkinson’s disease, and the neuropathology of carriers is heterogeneous and can include aberrant tau phosphorylation or tangles.  Recently, LRRK2 has been shown to phosphorylate tau in vitro; however,the major epitopes phosphorylated by LRRK2 and the pathogenic consequences of these modifications in vivo are unknown.  We identified multiple sites on recombinant tau that are phosphorylated by LRRK2 in vitro, including pT149 and pT153. Importantly, we demonstrate that expression of transgenic LRRK2 in rTg4510mice increased the aggregation of insoluble tau and its phosphorylation atT149, T153, T205, and S199/S202/T205 epitopes and increased neurodegeneration.  These findings indicate that tau can be aLRRK2 substrate and that this interaction can enhance salient features of human disease.
General Note:
In the series University of Florida Digital Collections.
General Note:
Includes vita.
Bibliography:
Includes bibliographical references.
Source of Description:
Description based on online resource; title from PDF title page.
Source of Description:
This bibliographic record is available under the Creative Commons CC0 public domain dedication. The University of Florida Libraries, as creator of this bibliographic record, has waived all rights to it worldwide under copyright law, including all related and neighboring rights, to the extent allowed by law.
Statement of Responsibility:
by Rachel M Bailey.
Thesis:
Thesis (Ph.D.)--University of Florida, 2013.
Local:
Adviser: LEWIS,JADA M.
Local:
Co-adviser: GIASSON,BENOIT IVAN.
Electronic Access:
RESTRICTED TO UF STUDENTS, STAFF, FACULTY, AND ON-CAMPUS USE UNTIL 2014-12-31

Record Information

Source Institution:
UFRGP
Rights Management:
Applicable rights reserved.
Classification:
lcc - LD1780 2013
System ID:
UFE0046079:00001