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, Hosseini AH, McDonald MP. Endogenous anxiety and stress responses in water maze and Barnes maze spatial memory tasks. Behav Brain Res. 2008 Oct 18; [Epub ahead of print] PMID: 18996418
• Ding Y, Qiao A, Wang Z, Goodwin JS, Lee ES, Block ML, Allsbrook M, McDonald MP, Fan GH. Retinoic acid attenuates beta-amyloid deposition and rescues memory deficits in an Alzheimer's disease transgenic mouse model. J Neurosci. 2008 Nov 5;28(45):11622-34. PMID: 18987198
• 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

view complete list of references (pubmed link)