Structural Remodeling of Alpha-Synuclein by Small Molecules : A Novel Path to Neuroprotective Therapeutics / Malcolm James Daniels.

Format:

Book

Thesis/Dissertation

Author/Creator:

Daniels, Malcolm James, author.

Contributor:

Ischiropoulos, Harry, degree supervisor.

University of Pennsylvania. Pharmacology, degree granting institution.

Language:

English

Subjects (All):

Pharmacology.

Neurosciences.

Biochemistry.

Pharmacology--Penn dissertations.

Penn dissertations--Pharmacology.

Local Subjects:

Pharmacology.

Neurosciences.

Biochemistry.

Pharmacology--Penn dissertations.

Penn dissertations--Pharmacology.

Genre:

Academic theses.

Physical Description:

1 online resource (176 pages)

Contained In:

Dissertation Abstracts International 80-01B(E).

Place of Publication:

[Philadelphia, Pennsylvania]: University of Pennsylvania ; Ann Arbor : ProQuest Dissertations & Theses, 2018.

Language Note:

English

System Details:

Mode of access: World Wide Web.

text file

Summary:

Neurodegenerative diseases share the unifying features of insoluble protein aggregates and irreversible neuron loss. Parkinson's disease (PD) is defined by proteinaceous Lewy bodies---which contain alpha-synuclein---and loss of dopamine neurons leading to motor dysfunction. Growing evidence implicates alpha-synuclein aggregation as a causal driver of neurodegeneration in certain forms of PD. However, the precise mechanism(s) by which the process or products of ?-synuclein aggregation drive neuron death remains unknown. Better understanding of this key question might further development of neuroprotective therapies for PD and related disorders. To address this gap, we reviewed how the native conformation of alpha-synuclein relates to its physiological function and roles in pathology. We also examined how the mouse brain proteome and phosphoproteome change in response to ?-synuclein aggregation using quantitative proteomics. This revealed that proteomic changes were not widespread, but instead were enriched within certain functional areas. For the first time, we found that the immunoproteasome is induced during aggregation, providing a new tunable target for studying alpha-synuclein aggregation and its connection to toxicity. We also employed nordihydroguaiaretic acid (NDGA) and analogs to study the chemistry and products of phenolic inhibitors of alpha-synuclein aggregation. We discovered that oxidation-dependent cyclization is required for NDGA analogs to inhibit alpha-synuclein aggregation and that this inhibition is caused by modification of alpha-synuclein monomers that retain their conformational dynamics and lipid interactions. Further, we found that these NDGA analog-modified monomers exert a dominant negative effect on aggregation of untreated alpha-synuclein, exposing a novel mechanism for inhibiting alpha-synuclein aggregation. Using transgenic Caenorhabditis elegans, we showed that cyclized NDGA can prevent neurodegeneration driven by alpha-synuclein. These findings outline a novel paradigm for small molecule inhibition of alpha-synuclein aggregation wherein they act by stabilizing dynamic alpha-synuclein monomers, preventing aggregation. This in turn prevents aggregation of untreated alpha-synuclein and reduces neurodegeneration. Together this work underscores the importance of alpha-synuclein's native structural dynamics and provides several novel tools for future use in untangling the relationship between alpha-synuclein aggregation and neuron loss in PD and related disorders.

Notes:

Source: Dissertation Abstracts International, Volume: 80-01(E), Section: B.

Advisors: Harry Ischiropoulos; Committee members: Kelly L. Jordan-Sciutto; Edward B. Lee; Kelvin C. Luk; E. James Petersson.

Department: Pharmacology.

Ph.D. University of Pennsylvania 2018.

Local Notes:

School code: 0175

ISBN:

9780438421868

Access Restriction:

Restricted for use by site license.