عنوان

A Role for Cytoskeletal Proteins as Modifiers of Mutant Huntingtin Toxicity

Number

TL5q82m1wm

.Language of Text, Soundtrack etc

انگلیسی

Title Proper

A Role for Cytoskeletal Proteins as Modifiers of Mutant Huntingtin Toxicity

General Material Designation

[Thesis]

First Statement of Responsibility

Zahed Kargaran, Hengameh

Subsequent Statement of Responsibility

Finkbeiner, Steven M.

Name of Publisher, Distributor, etc.

UCSF

Date of Publication, Distribution, etc.

2014

Body granting the degree

UCSF

Text preceding or following the note

2014

Text of Note

Huntington's disease (HD) is an adult-onset monogenic neurodegenerative disorder that can manifest with any combination of motor, cognitive, and psychiatric symptoms. Despite two decades of research since the discovery of the gene, our current understanding of HD pathogenic mechanisms remains incomplete and no disease-modifying therapies exist. A large number of pathogenic mechanisms have been implicated in HD, but the relative importance or order and timing of these processes are still a matter of much debate. Studies in another neurodegenerative disorder, Alzheimer's disease (AD), have shown that deleting the microtubule associated-protein tau reverses cognitive deficits and behavioral abnormalities in multiple AD models, potentially by blocking disease-related synaptic hyper-excitability without affecting normal synaptic transmission. Since excitotoxicity may also contribute to the pathogenesis of HD, we examined whether deleting tau can also prevent abnormalities in a mouse model of HD. Using the BACHD model, we present evidence that deleting tau ameliorates some HD-induced behavioral and neuropathological symptoms. We also explored the extent of transcriptional dysregulation in this mouse model. While we found little evidence for large-scale perturbations in the transcriptional profile of these mice early in their disease progression, we discovered that the actin-bundling protein alpha-Actinin2 (ACTN2) is down-regulated in BACHD brains. As TAU and ACTN2 are both cytoskeleton-associated proteins, our work suggests that perturbations in the cytoskeleton may be involved in HD-induced pathogenesis.

Zahed Kargaran, Hengameh

Finkbeiner, Steven M.

UCSF

Electronic name

p

[Thesis]

276903

a

Y