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Carnosine as a Mechanism-based Intervention in the Thy1-aSyn Mouse Model of Parkinson’s Disease: Neurobehavioral, Biochemical, and Bioinformatic Analyses

Bermúdez, Mei-Ling
http://orcid.org/0000-0001-8748-747X
http://rave.ohiolink.edu/etdc/view?acc_num=ucin1543839362404126

Abstract Details

2018, PhD, University of Cincinnati, Medicine: Toxicology (Environmental Health).
Parkinson's disease (PD) is the most common motor neurodegenerative disease worldwide, affecting millions of people. No cure exists for this devastating disease, which is characterized by non-motor and motor deficits, including resting tremor, gait instability, and decreased olfactory function. Hallmarks of PD include protein aggregates and the loss of dopaminergic neurons in the substantia nigra. PD is attributed to molecular mechanisms including oxidative stress, and mitochondrial dysfunction. These studies evaluated a novel, mechanism-based intervention for PD, using the Thy1-aSyn mouse model of PD, which overexpresses human wild-type alpha-synuclein (aSyn). These mice exhibit progressive non-motor and motor deficits as early as 2 months of age. The dipeptide carnosine was selected as an intervention based on its potential to enhance mitochondrial function, protect against oxidative stress, and reduce protein aggregation, which are key features of PD. In addition, carnosine in drinking water (DW) was previously reported to decrease protein aggregation in a mouse model of Alzheimer’s disease. The intranasal (IN) route is known as an effective means to administer therapeutics to the brain; therefore we compared IN and DW routes of carnosine exposure. The aims of this research project tested the hypothesis that IN administration of carnosine would significantly slow the progression of PD in Thy1-aSyn mice. Two-month old wild-type and Thy1-aSyn mice were treated with IN and DW carnosine, with controls receiving sterile waster intranasally or carnosine-free DW daily, respectively. After two months of treatment, the effects of carnosine were evaluated using bioinformatic, neurobehavioral, and biochemical analysis. The transcriptomic profile revealed that ribosomal and mitochondrial deficiencies associated with aSyn overexpression in Thy1-aSyn mice were attenuated by IN-carnosine administration in the midbrain. In addition to increasing the expression of mitochondrial genes, IN-carnosine increased the protein levels of complex V, complex IV activity, and mitochondrial function in Thy1-aSyn carnosine-treated mice compared to vehicle-treated controls. Motor and olfactory functions were tested with the challenging beam traversal (CBT) and the buried pellet (BP) tests, respectively, at the beginning and the end of the treatment period. In the CBT test, IN treated Thy1-aSyn committed fewer errors per step compared to vehicle-treated Thy1-aSyn mice. Olfactory function and tissue were preserved, and reduced levels of aSyn-positive inclusion were detected in the olfactory epithelium (OE) of IN-treated Thy-aSyn mice compared to Thy1-aSyn vehicle controls. For all endpoints studied, IN-carnosine performed superior to DW carnosine. Based on the beneficial results observed in young mice treated with IN-carnosine, studies were repeated in a subset of 8-month-old mice. At baseline, 8-month-old transgenic mice showed a progressive sensorimotor dysfunction, compared with 2-month-old mice. The results of this pilot study with aged mice corroborated the initial findings in the young mice, where IN-carnosine protected sensorimotor function and reduced aSyn-positive immunostaining in the OE. Our findings in young and aged mice showed that IN-carnosine prevented progression of sensorimotor deficits and aSyn aggregation in the Thy1-aSyn model of PD. Overall, IN-carnosine shows promise to slow the progression of sensorimotor deficits, prevent aberrant protein deposition, and enhance mitochondrial function in PD patients.
Mary Beth Genter, Ph.D. (Committee Chair)
Katherine Burns, Ph.D. (Committee Member)
John Oblong, Ph.D. (Committee Member)
Kim Seroogy, Ph.D. (Committee Member)
Matthew Skelton, Ph.D. (Committee Member)
145 p.
Toxicology
Parkinsons disease; Alpha-synuclein; Intranasal; Carnosine; Thy-aSyn mice; Mitochondria

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Citations

  • Bermúdez, M.-L. (2018). Carnosine as a Mechanism-based Intervention in the Thy1-aSyn Mouse Model of Parkinson’s Disease: Neurobehavioral, Biochemical, and Bioinformatic Analyses [Doctoral dissertation, University of Cincinnati]. OhioLINK Electronic Theses and Dissertations Center. http://rave.ohiolink.edu/etdc/view?acc_num=ucin1543839362404126

    APA Style (7th edition)

  • Bermúdez, Mei-Ling. Carnosine as a Mechanism-based Intervention in the Thy1-aSyn Mouse Model of Parkinson’s Disease: Neurobehavioral, Biochemical, and Bioinformatic Analyses. 2018. University of Cincinnati, Doctoral dissertation. OhioLINK Electronic Theses and Dissertations Center, http://rave.ohiolink.edu/etdc/view?acc_num=ucin1543839362404126.

    MLA Style (8th edition)

  • Bermúdez, Mei-Ling. "Carnosine as a Mechanism-based Intervention in the Thy1-aSyn Mouse Model of Parkinson’s Disease: Neurobehavioral, Biochemical, and Bioinformatic Analyses." Doctoral dissertation, University of Cincinnati, 2018. http://rave.ohiolink.edu/etdc/view?acc_num=ucin1543839362404126

    Chicago Manual of Style (17th edition)

ucin1543839362404126
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This open access ETD is published by University of Cincinnati and OhioLINK.