Michael P. McDonald, Ph.D.
Department of Neurology
The University of Tennessee Health Science Center
855 Monroe Avenue, Suite 415
Memphis, TN 38163
Phone: (901) 448-4648
Fax: (901) 448-4685
Office: 422 Wittenborg Anatomy Building
Email: Michael P. McDonald
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-β (Aβ), 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 Aβ binding and Aβ -induced cell death in primary neuronal cultures. In a mutant mouse model of Alzheimer's disease, knocking out GD3S nearly eliminates plaque formation and Aβ -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 Aβ, and increasing levels of the less-complex brain gangliosides, which have a lower affinity for Aβ and are neuroprotective. We expect this line of research to provide insight into new therapeutic targets for Alzheimer's and Parkinson's diseases.
- Ariga T, Itokazu Y, McDonald MP, Hirabayashi Y, Ando S, Yu RK. Brain gangliosides of a transgenic mouse model of Alzheimer's disease with deficiency in GD3-synthase: Expression of elevated levels of a cholinergic specific ganglioside, GT1aÎ±. ASN Neuro. 2013 Apr 8. [Epub ahead of print] PubMed PMID: 23565921.
- Dhanushkodi A, Akano EO, Roguski EE, Xue Y, Rao SK, Matta SG, Rex TS, McDonald MP. A single intramuscular injection of rAAV-mediated mutant erythropoietin protects against MPTP-induced parkinsonism. Genes Brain Behav. 2013 Mar;12(2):224-33. doi: 10.1111/gbb.12001. Epub 2012 Nov 28. PubMed PMID: 23190369.
- Petchsang N, McDonald MP, Sinks LE, Kuno M. Light induced nanowire assembly: the electrostatic alignment of semiconductor nanowires into functional macroscopic yarns. Adv Mater. 2013 Jan 25;25(4):601-5. doi: 10.1002/adma.201202722. Epub 2012 Oct 2. PubMed PMID: 23027517.
- Dhanushkodi A, McDonald MP. Intracranial V. cholerae sialidase protects against excitotoxic neurodegeneration. PLoS One. 2011;6(12):e29285. doi: 10.1371/journal.pone.0029285. Epub 2011 Dec 15. PubMed PMID: 22195039; PubMed Central PMCID: PMC3240658.
- Giblin J, Vietmeyer F, McDonald MP, Kuno M. Single nanowire extinction spectroscopy. Nano Lett. 2011 Aug 10;11(8):3307-11. doi: 10.1021/nl201679d. Epub 2011 Jul 22. PubMed PMID: 21770437.
- Ariga T, Yanagisawa M, Wakade C, Ando S, Buccafusco JJ, McDonald MP, Yu RK. Ganglioside metabolism in a transgenic mouse model of Alzheimer's disease: expression of Chol-1Î± antigens in the brain. ASN Neuro. 2010 Oct 4;2(4):e00044. doi: 10.1042/AN20100021. PubMed PMID: 20930939; PubMed Central PMCID: PMC2948441.