Identification and characterization of the Drosophila tau homologue.

Format:

Book

Thesis/Dissertation

Author/Creator:

Heidary, Gena.

Contributor:

Fortini, Mark E., advisor.

University of Pennsylvania.

Language:

English

Subjects (All):

Genetics.

Neurosciences.

0317.

0369.

Penn dissertations--Neuroscience.

Neuroscience--Penn dissertations.

Local Subjects:

Penn dissertations--Neuroscience.

Neuroscience--Penn dissertations.

0317.

0369.

Physical Description:

131 pages

Contained In:

Dissertation Abstracts International 64-04B.

System Details:

Mode of access: World Wide Web.

text file

Summary:

A pathological hallmark of neurodegenerative tauopathies, including Alzheimer's disease and the frontotemporal dementias, is the presence of intracellular neurofibrillary tangles. The principal component of these structures is the microtubule-associated protein (MAP) tau that in these deposits, is abnormally phosphorylated, insoluble and redistributed from the axonal to the somatodendritic compartments of neurons. The identification of mutations in the tau locus in patients with familial frontotemporal dementias has demonstrated that mutations in tau are sufficient to cause neurodegenerative disease. Whether neuronal loss occurs due to the presence of aggregated tau or due to the loss of normal tau activity, or both, still remains unanswered. To address these issues, we have used a complementary approach of loss-of-function and overexpression studies in the genetic model organism Drosophila melanogaster.

We present molecular and genetic analysis of a novel Drosophila gene, tau which we have concluded is the homologue of the mammalian MAP tau gene on the basis of sequence homology, phylogenetic data and the apparent molecular weight of the protein. The fly tau protein is expressed in development throughout the CNS and in specific neuronal accessory cells in the PNS called cap cells. In larval and adult stages, we find tau protein in photoreceptor neurons as well as in the nurse and follicle cells of the ovary.

Genetic analysis of loss-of-function mutations in the fly tau reveals that fly tau is an essential gene. Our results support distinct roles for tau in normal neuronal development and in adult viability. Homozygous tau mutant flies exhibit neuronal patterning defects of the PNS during embryogenesis. Loss of tau function impairs normal synaptic transmission in larval motor neurons and this may be linked to abnormal locomotor behavior in mutant larvae.

Using a targeted overexpression strategy of the human tau protein, we can recapitulate features of tau-related pathology including the accumulation of insoluble, abnormally phosphorylated tau that is associated with cell death. Courtship analysis of these tau transgenic flies reveals a functional impairment of short-term memory. This model system presents a powerful tool for the performance of modifier screens to identify molecules involved in the pathogenesis of tau-induced neurodegeneration.

Notes:

Thesis (Ph.D. in Neuroscience) -- University of Pennsylvania, 2003.

Source: Dissertation Abstracts International, Volume: 64-04, Section: B, page: 1636.

Superviser: Mark E. Fortini.

Local Notes:

School code: 0175.

ISBN:

9780496351787

Access Restriction:

Restricted for use by site license.