MICHAEL P. MCDONALD, Ph.D.

Assistant Professor

Department of Neurology

The University of Tennessee Health Science Center

Address

The University of Tennessee Health Science Center

855 Monroe Avenue, Suite 415

Memphis, TN 38163

Tel: (901) 448-4648; Fax: (901) 448-4685;

Office: 422 Wittenborg Anatomy Building

Research Interests

Our lab studies the involvement of gangliosides in the behavioral and cognitive impairments, protein misfolding, and neurodegeneration of Alzheimer’s and Parkinson’s diseases. Gangliosides are glycolipids richly expressed in neuronal membranes. Although the functions of gangliosides are not completely understood, converging evidence clearly demonstrates a critical role for membrane gangliosides in the binding and aggregation of amyloid-ß (Aß), the toxic peptide that aggregates into plaques in Alzheimer’s disease. Our previous research showed that elimination of the GD3 synthase (GD3S) gene significantly reduces Aß binding and Aß-induced cell death in primary neuronal cultures. In a mutant mouse model of Alzheimer’s disease, knocking out GD3S nearly eliminates plaque formation and Aß-associated neuropathology, and reverses memory deficits. Because GD3 ganglioside is a critical mediator of the ceramide-sphingomyelin-mediated apoptotic pathway, we expect that inhibiting GD3S will also be neuroprotective in models of Parkinson’s disease. In addition to targeted mutation of GD3S, ongoing experiments involve injection of viral-vector-mediated small-interfering RNA (siRNA) constructs to “silence” GD3S, and intracranial infusion of v. cholerae sialidase (VCS), an enzyme that hydrolyzes specific sialic acid residues on gangliosides. Both of these manipulations have the effect of reducing levels of the more-complex brain gangliosides, which have a high affinity for Aß, and increasing levels of the less-complex brain gangliosides, which have a lower affinity for Aß and are neuroprotective. We expect this line of research to provide insight into new therapeutic targets for Alzheimer’s and Parkinson’s diseases.

Recent Publications

• Harrison FE, Yu SS, Van Den Bossche KL, Li L, May JM, McDonald MP. Elevated oxidative stress and sensorimotor deficits but normal cognition in mice that cannot synthesize ascorbic acid. J Neurochem. 2008 Aug;106(3):1198-208. Epub 2008 May 7. PMID: 18466336
• Ariga T, McDonald MP, Yu RK. Role of ganglioside metabolism in the pathogenesis of Alzheimer's disease--a review. J Lipid Res. 2008 Jun;49(6):1157-75. Epub 2008 Mar 11. Review. PMID: 18334715
• Bernardo A, Harrison FE, McCord M, Zhao J, Bruchey A, Davies SS, Jackson Roberts L 2nd, Mathews PM, Matsuoka Y, Ariga T, Yu RK, Thompson R, McDonald MP. Elimination of GD3 synthase improves memory and reduces amyloid-beta plaque load in transgenic mice. Neurobiol Aging. 2008 Feb 5; [Epub ahead of print] PMID: 18258340
• Reiserer RS, Harrison FE, Syverud DC, McDonald MP. Impaired spatial learning in the APPSwe + PSEN1DeltaE9 bigenic mouse model of Alzheimer's disease. Genes Brain Behav. 2007 Feb;6(1):54-65. PMID: 17233641
• Harrison FE, Reiserer RS, Tomarken AJ, McDonald MP. Spatial and nonspatial escape strategies in the Barnes maze. Learn Mem. 2006 Nov-Dec;13(6):809-19. Epub 2006 Nov 13. PMID: 17101874
• Bazalakova MH, Wright J, Schneble EJ, McDonald MP, Heilman CJ, Levey AI, Blakely RD. Deficits in acetylcholine homeostasis, receptors and behaviors in choline transporter heterozygous mice. Genes Brain Behav. 2007 Jul;6(5):411-24. Epub 2006 Sep 8. PMID: 17010154

view complete list of references (pubmed link)