Marcy E. MacDonald, Ph.D.

Department of Neurology
Massachusetts General Hospital
Richard B. Simches Research Center
CPZN-5414
185 Cambridge St.
Boston, MA 02114
Tel: (617) 726-5089
Fax: (617) 726-5735
Email: macdonam@helix.mgh.harvard.edu
Webpage: The MacDonald Lab Page
6 postdoctoral fellows

We are using a molecular genetic approach to understand inherited human neurodegenerative diseases. Two major interests, for which we have identified the gene defects and have made genetically accurate mouse and neuronal cell models, are Huntington's disease (HD) and Neuronal Ceroid Lipofuscinoses (NCLs).

HD is a dominant adult onset disorder that features the loss of striatal neurons. The HD gene encodes an expanded polyglutamine tract in huntingtin, a nuclear-cytoplasmic protein that may organize members of signaling complexes. Studies in Hdhex4/5 knock-out mice show that huntingtin is needed for gastrulation and CNS development. Studies in Hdh CAG knock-in mice and STHdhQ111 striatal cells reveal that, while retaining its intrinsic activities, mutant huntingtin leads to dominant events that presage overt pathology (eg. mitochondrial dysfunction, altered signaling states).

The NCLs are recessive disorders of childhood that feature the loss of retinal and CNS neurons . CLN6 encoded linclin and CLN3 encoded batten are required for normal mitochondrial autophagy. Linclin is an ER membrane protein that we are investigating in the nclf mouse, which carries a spontaneous Cln6 mutation. Battenin is an endosomal protein that interacts with membrane/cytoskeletal partners. Studies in Cln3del7/8 knock-in mouse and CbCln3del7/8 cerebellar cells indicate that battenindel7/8 leads to recessive phenotypes that precede ATP subunit c accumulation in autophagosomes (eg. abnormal processing of lysosomal preproenzymes, altered mTOR signaling). We continue to delineate and determine the temporal order of early steps in the HD and NCL disease pathways and we are pursuing genetic variants and small molecules that modulate the disease process.

References:

• Gines S, Seong IS, Fossale E, Ivanova E, Trettel F, Gusella JF, Wheeler VC, Persichetti F, MacDonald ME. Specific progressive cAMP reduction implicates energy deficit in presymptomatic Huntington's disease knock-in mice. Hum Mol Genet. 2003;12(5):497-508.
• Fossale E, Wolf P, Espinola JA, Lubicz-Nawrocka T, Teed AM, Gao H, Rigamonti D, Cattaneo E, MacDonald ME, Cotman SL. Membrane trafficking and mitochondrial abnormalities precede subunit c deposition in a cerebellar cell model of juvenile neuronal ceroid lipofuscinosis. BMC Neurosci. 2004;5(1):57.
• Seong IS, Ivanova E, Lee JM, Choo YS, Fossale E, Anderson M, Gusella JF, Laramie JM, Myers RH, Lesort M, Macdonald ME. The HD CAG Repeat Implicates a Dominant Property of Huntingtin in Mitochondrial Energy Metabolism. Hum Mol Genet. 2005; 14(19):2871-80.
• Woda JM, Calzonetti T, Hilditch-Maguire P, Duyao MP, Conlon RA, Macdonald ME. Inactivation of the Huntington's disease gene (Hdh) impairs anterior streak formation and early patterning of the mouse embryo. BMC Dev Biol. 2005; 5:17.