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Exploring the Potential of 20S Prote...

Vanecek, Allison Stephanie,

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Exploring the Potential of 20S Proteasome Modulation as a Novel Therapeutic Strategy for the Treatment of Neurodegenerative Diseases and Cancers /

Record Type:	Electronic resources : Monograph/item
Title/Author:	Exploring the Potential of 20S Proteasome Modulation as a Novel Therapeutic Strategy for the Treatment of Neurodegenerative Diseases and Cancers // Allison Stephanie Vanecek.
Author:	Vanecek, Allison Stephanie,
Description:	1 electronic resource (237 pages)
Notes:	Source: Dissertations Abstracts International, Volume: 86-02, Section: B.
Contained By:	Dissertations Abstracts International86-02B.
Subject:	Chemistry. -
Online resource:	https://pqdd.sinica.edu.tw/twdaoapp/servlet/advanced?query=31144413
ISBN:	9798383696361

Exploring the Potential of 20S Proteasome Modulation as a Novel Therapeutic Strategy for the Treatment of Neurodegenerative Diseases and Cancers /
Vanecek, Allison Stephanie,

Exploring the Potential of 20S Proteasome Modulation as a Novel Therapeutic Strategy for the Treatment of Neurodegenerative Diseases and Cancers /Allison Stephanie Vanecek. - 1 electronic resource (237 pages)

Source: Dissertations Abstracts International, Volume: 86-02, Section: B.

The accumulation of intrinsically disordered proteins (IDPs) and the associated disruption of cellular proteostasis is implicated in the progression of a number of neurodegenerative diseases and cancers. Due to the highly disordered nature of IDPs, they are considered "undruggable" targets because of their lack of typical drug binding pockets. The work in this dissertation focuses on the exploration of an alternative approach to pharmacologically regulate these "undruggable" proteins through proteasome-mediated degradation. The 20S proteasome is a large protein degradation complex responsible for maintaining low cellular levels of IDPs. Our approach uses small molecule enhancers of proteolytic activity of the 20S proteasome to enhance the degradation of IDPs, thereby preventing their accumulation and associated toxicity.To demonstrate the potential use of small molecule 20S activation as a novel therapeutic approach for the treatment of neurodegenerative diseases, we studied the effects of a 20S proteasome activator toward an IDP target associated with the progression of amyotrophic lateral sclerosis (ALS). Recently, 30 to 60 percent of familial ALS cases have been linked to a gene mutation that results in the production of five highly disordered dipeptide repeat (DPR) proteins. The accumulation and aggregation of DPRs have shown to disrupt cellular proteostasis, leading to uncontrolled protein levels, resulting in neuron death and further disease progression. In a recent collaborative study, we have demonstrated that 20S proteasome activator, TCH-165, enhances the degradation of DPR proteins. The enhanced degradation of DPR proteins led to the restoration of cellular proteostasis and provided protection against DPR induced neurotoxicity in ALS disease models.We then aimed to explore the potential use of small molecule 20S activation as a novel therapeutic strategy for cancer treatment. The overexpression of the highly disordered transcription factor, c-MYC, has been found in more than 70 percent of all human cancers. Dysregulation of c-MYC protein levels and its accumulation has shown to induce its oncogenic transcriptional activity, resulting in the transcription of a number of genes that promote tumor growth and cancer cell proliferation. In a recent study, we demonstrated the ability of TCH-165 to reduce cellular c-MYC protein levels. The enhanced degradation of c-MYC prevented its oncogenic effects, inhibiting cancer cell proliferation and reducing tumor growth in vivo.To further explore this therapeutic strategy, a novel class of 20S proteasome activators was identified and synthetically modified to generate a series of analogues. Through investigation of the biological activities of this new class of 20S proteasome activators, a new component of the therapeutic mechanism was discovered. These findings provide evidence that activation of the 20S proteasome can be tuned to selectively target IDPs based on their amino acid sequence. This suggests the exciting possibility that a small molecule 20S proteasome activator could be designed to selectively target a specific IDP for a more targeted disease treatment. In all, this work suggests that small molecule activation of the 20S proteasome may offer a potential novel therapeutic strategy for the treatment of neurodegenerative diseases and cancers in which intrinsically disordered protein accumulation plays a significant role in disease progression.

English

ISBN: 9798383696361Subjects--Topical Terms:

516420
Chemistry.
Subjects--Index Terms:

Intrinsically disordered proteins

Exploring the Potential of 20S Proteasome Modulation as a Novel Therapeutic Strategy for the Treatment of Neurodegenerative Diseases and Cancers /
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