Effects of the polyglutamine neurodegenerative protein ataxin-3 on transcriptional regulation and the ubiquitin-proteasome pathway / Fusheng Li.

Format:

Book

Manuscript

Microformat

Thesis/Dissertation

Author/Creator:

Li, Fusheng.

Contributor:

Pittman, Randall N., advisor.

University of Pennsylvania.

Language:

English

Subjects (All):

Penn dissertations--Pharmacological sciences.

Pharmacological sciences--Penn dissertations.

Pharmacological Sciences.

Academic Dissertations as Topic.

Medical Subjects:

Pharmacological Sciences.

Academic Dissertations as Topic.

Local Subjects:

Penn dissertations--Pharmacological sciences.

Pharmacological sciences--Penn dissertations.

Physical Description:

xii, 127 pages : illustrations ; 29 cm

Production:

2003.

Summary:

Spinocerebellar ataxia type 3 (SCA3) results from expansion of a glutamine stretch in the disease protein, ataxin-3. SCA3 belongs to the polyglutamine disease family, for which the pathogenic mechanism remains elusive. Ataxin-3 is widely distributed in all human tissues and its amino acid composition is conserved, suggesting that it may have an important physiological function; although, its function is unknown. A major objective of my thesis was to identify potential functions of ataxin-3 with the expectation that this will help us understand the pathology in SCA3 as well as other polyglutamine diseases. Major findings from my thesis study include identifying potential functions of ataxin-3 in transcriptional regulation and in the ubiquitin-proteasome pathway. Ataxin-3 interacts with the major histone acetyltransferases CBP, p300, and PCAF and inhibits transcription by these coactivators. Importantly, endogenous ataxin-3 is co-immunoprecipitated with each of these coactivators. The C-terminal polyglutamine-containing domain of ataxin-3 inhibits coactivator-dependent transcription and is required for binding coactivators. A traditional corepressor function appears to be the mechanism of this repression. The N-terminal domain of ataxin-3 inhibits histone acetylation and inhibits transcription. Histone binding and blocking access of coactivators to acetylation sites on histones appears to be the mechanism of inhibition. Together, these data provide a novel mechanism of transcriptional regulation by ataxin-3 that involves targeting histones, coactivators and an independent mode of direct repression of transcription, and suggests that its physiological function and possibly pathological effects are linked to its interactions with these proteins. Ataxin-3 also binds to polyubiquitylated proteins with a strong preference for chains containing four or more ubiquitins. The interaction is mediated by two ubiquitin interaction motifs (UIMs) based on assays using truncated proteins and site-directed mutagenesis. Ataxin-3 inhibits ubiquitylation of 125I-lysozyme as well as unlabeled cellular substrates. Whereas inhibition of ubiquitylation by wild-type ataxin-3 is limited to inhibiting long chain polyubiquitylation, pathological AT3 also inhibits mono-/short chain ubiquitylation. This additional property of pathological ataxin-3 may represent one aspect of the gain of function associated with the pathological protein.

Notes:

Supervisor: Randall N. Pittman.

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

Includes bibliographical references.

Local Notes:

University Microfilms order no.: 3095910.

OCLC:

244973659