BBS Faculty Member - Marcy MacDonald

Marcy MacDonald

Department of Neurology

Massachusetts General Hospital
Richard B. Simches Research Ctr, CPZN-5414
185 Cambridge St.
Boston, MA 02114
Tel: 617-726-5089
Fax: 617-726-5735
Email: macdonam@helix.mgh.harvard.edu
Lab Members: 6 postdoctoral fellows
Visit my lab page here.



We are using molecular genetic approaches in humans and knock-in mice, with precisely targeted gene mutations, to understand the basis of inherited human neurodegenerative diseases. Two major interests, where we have identified the underlying gene defects and have made genetically accurate mouse and neuronal cell models, are Huntington’s disease (HD) and Neuronal Ceroid Lipofuscinosis (NCLs).

HD is a dominant, typically adult onset disorder that features the loss of striatal neurons. The HD gene defect expands, into the disease-causing range, a functional CAG triplet repeat polymorphism. This repeat encodes a polyglutamine tract that quantitatively alters the structure and enhances the function of huntingtin, an ancient 350 kDa alpha-helical HEAT domain protein that serves to organize members of macromolecular complexes.

The NCLs are recessive disorders of childhood that feature the loss of retinal and CNS neurons, with the timing of onset of symptoms determined by the CLN gene involved and the particular loss of function mutation. The CLN genes encode different small transmembrane proteins of, for example, the endoplasmic reticulum or the lysosomal system, involved in autophagy.

Our studies favor global unbiased strategies for investigating the normal functions of the disease genes and the immediate effects of the disease-causing mutations, such as genetic screens for modifying loci, whole genome RNA expression, proteomics and metabolomic analyses, but also extend to testing hypotheses using biochemical approaches, for example protein purification and the generation of activity assays.



Last Update: 8/22/2013



Publications

For a complete listing of publications click here.

 


 

Lee JM, Ivanova EV, Seong IS, Cashorali T, Kohane I, Gusella JF, MacDonald ME. Unbiased gene expression analysis implicates the huntingtin polyglutamine tract in extra-mitochondrial energy metabolism. PLoS Genet. 2007 3(8):e135.

Seong IS, Woda JM, Song JJ, Lloret A, Abeyrathne PD, Woo CJ, Gregory G, Lee JM, Wheeler VC, Walz T, Kingston RE, Gusella JF, Conlon RA, MacDonald ME. Huntingtin facilitates polycomb repressive complex 2. Hum Mol Genet. 2010 19(4):573-83.

Cao Y, Staropoli JF, Biswas S, Espinola JA, MacDonald ME, Lee JM, Cotman SL. Distinct Early Molecular Responses to Mutations Causing vLINCL and JNCL Presage ATP Synthase Subunit C Accumulation in Cerebellar Cells. PLoS One. 2011 6(2):e17118.

Reis SA, Thompson MN, Lee JM, Fossale E, Kim HH, Liao JK, Moskowitz MA, Shaw SY, Dong L, Haggarty SJ, MacDonald ME, Seong IS. Striatal neurons expressing full-length mutant huntingtin exhibit decreased N-cadherin and altered neuritogenesis. Hum Mol Genet. 2011 20(12):2344-55.

Jacobsen JC, Gregory GC, Woda JM, Thompson MN, Coser KR, Murthy V, Kohane IS, Gusella JF, Seong IS, MacDonald ME, Shioda T, Lee JM. HD CAG-correlated gene expression changes support a simple dominant gain of function. Hum Mol Genet. 2011 20(14):2846-60.



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