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Michael P. McDonald, PhD

Associate Professor
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
Email: Michael P. McDonald

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-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.

Representative Publications

  • Li L, Ismael S, Nasoohi S, Sakata K, Liao FF, McDonald MP, Ishrat T. Thioredoxin-Interacting Protein (TXNIP) Associated NLRP3 Inflammasome Activation in Human Alzheimer's Disease Brain. J Alzheimer's Dis. 2019;68(1):255-265. doi: 10.3233/JAD-180814. PubMed PMID: 30741672.
  • Dhanushkodi A, Xue Y, Roguski EE, Ding Y, Matta SG, Heck D, Fan GH, McDonald MP. Lentiviral-mediated knock-down of GD3 synthase protects against MPTP-induced motor deficits and neurodegeneration. Neurosci Lett. 2019 Jan 23;692:53-63. doi: 10.1016/j.neulet.2018.10.038. Epub 2018 Nov 1. PubMed PMID: 30391320; PubMed Central PMCID: PMC6372990.
  • Kulas JA, Hettwer JV, Sohrabi M, Melvin JE, Manocha GD, Puig KL, Gorr MW, Tanwar V, McDonald MP, Wold LE, Combs CK. In utero exposure to fine particulate matter results in an altered neuroimmune phenotype in adult mice. Environ Pollut. 2018 Oct;241:279-288. doi: 10.1016/j.envpol.2018.05.047. Epub 2018 May 22. PubMed PMID: 29843010; PubMed Central PMCID: PMC6082156.
  • Wang B, Liu Y, Huang L, Chen J, Li JJ, Wang R, Kim E, Chen Y, Justicia C, Sakata K, Chen H, Planas A, Ostrom RS, Li W, Yang G, McDonald MP, Chen R, Heck DH, Liao FF. Hsp90 inhibitor induces nuclear translocation of HSF1 predominantly in hippocampal CA1 region. Mol Psychiatry. 2017 Jul;22(7):935. doi: 10.1038/mp.2017.125. PubMed PMID: 28638149.
  • Akkhawattanangkul Y, Maiti P, Xue Y, Aryal D, Wetsel WC, Hamilton D, Fowler SC, McDonald MP. Targeted deletion of GD3 synthase protects against MPTP-induced neurodegeneration. Genes Brain Behav. 2017 Jun;16(5):522-536. doi: 10.1111/gbb.12377. Epub 2017 Apr 18. PubMed PMID: 28239983; PubMed Central PMCID: PMC5543812.
  • Wang B, Liu Y, Huang L, Chen J, Li JJ, Wang R, Kim E, Chen Y, Justicia C, Sakata K, Chen H, Planas A, Ostrom RS, Li W, Yang G, McDonald MP, Chen R, Heck DH, Liao FF. A CNS-permeable Hsp90 inhibitor rescues synaptic dysfunction and memory loss in APP-overexpressing Alzheimer's mouse model via an HSF1-mediated mechanism. Mol Psychiatry. 2017 Jul;22(7):990-1001. doi: 10.1038/mp.2016.104. Epub 2016 Jul 26. PubMed PMID: 27457810; PubMed Central PMCID: PMC5323357.

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May 26, 2022