The toxic interaction of dopamine and alpha-synuclein: Implications for Parkinson's disease / Mor, Danielle Emille.

Format:

Book

Thesis/Dissertation

Author/Creator:

Mor, Danielle Emille, author.

Contributor:

Kalb, Robert, degree supervisor.

Ischiropoulos, Harry, degree supervisor.

Przedborski, Serge, degree committee member.

Lee, Virginia, degree committee member.

Jordan-Sciutto, Kelly, degree committee member.

Bonini, Nancy, degree committee member.

University of Pennsylvania. Neuroscience, degree granting institution.

Language:

English

Subjects (All):

Neurosciences.

Neuroscience--Penn dissertations.

Penn dissertations--Neuroscience.

Local Subjects:

Neurosciences.

Neuroscience--Penn dissertations.

Penn dissertations--Neuroscience.

Genre:

Academic theses.

Physical Description:

1 online resource (163 pages)

Contained In:

Dissertation Abstracts International 78-07B(E).

Place of Publication:

[Philadelphia, Pennsylvania] : University of Pennsylvania ; Ann Arbor : ProQuest Dissertations & Theses, 2016.

Language Note:

English

System Details:

Mode of access: World Wide Web.

text file

Summary:

Neurodegenerative disorders are characterized by the death of specific neuronal populations and the aggregation of particular proteins into pathological inclusions. The role of protein aggregation and the factors that govern neuronal susceptibility to disease have remained unclear. In Parkinson's disease (PD), the loss of dopamine producing neurons in the substantia nigra (SN) leads to severe motor impairments, and the protein alpha-synuclein is found aggregated in several brain regions including the SN. The goal of this thesis was to investigate a possible mechanism for the vulnerability of dopaminergic neurons: the interaction of alpha-synuclein with dopamine itself. While dopamine has been suspected to contribute to cell death in PD by causing oxidative stress, I found using a lentiviral approach that a long-term increase of dopamine levels in non-transgenic mice was insufficient to produce dopamine neuron loss. In contrast, elevating dopamine in mice expressing human alpha-synuclein resulted in progressive nigrostriatal degeneration and an associated locomotor deficit. These findings demonstrate that dopamine toxicity is dependent on alpha-synuclein. To explore a possible point of convergence of these two factors, I examined the effects of dopamine on alpha-synuclein aggregation in the mouse brain. This led to the novel observation that dopamine increases total steady-state levels of alpha-synuclein oligomers and promotes modified oligomeric conformations. alpha-synuclein oligomers generated in the presence of dopamine in vitro were biochemically similar to mouse-derived species and were found to be toxic to primary neurons. Taken together, these data provide evidence that dopamine-induced alpha-synuclein oligomers may underlie the susceptibility of dopaminergic neurons in disease.

Notes:

Source: Dissertation Abstracts International, Volume: 78-07(E), Section: B.

Advisors: Harry Ischiropoulos; Robert Kalb; Committee members: Nancy Bonini; Kelly Jordan-Sciutto; Virginia Lee; Serge Przedborski.

Department: Neuroscience.

Ph.D. University of Pennsylvania 2016.

Local Notes:

School code: 0175

ISBN:

9781369510881

Access Restriction:

Restricted for use by site license.