James Gusella headshot

James Francis Gusella, Ph.D.

Bullard Professor of Neurogenetics in the Department of Genetics, Harvard Medical School
Research Staff, Massachusetts General Hospital

My laboratory is focused on understanding nervous system disease using molecular genetic strategies, beginning with human patients and proceeding through in vitro and modeling studies, with the ultimate goal of improving diagnosis, management and treatment.In any given disorder, the research can usually be divided into four sequential stages:

1. Determination of the chromosomal location of a gene defect, susceptibility gene or genetic modifier, usually based on linkage or association studies with polymorphic genetic markers.
2. Identification of the gene responsible for the phenotypic effect based upon its chromosomal location using a variety of genome analysis strategies.
3. Characterization of the mechanism of action based upon analysis of the allelic versions of the culprit gene in man, and in appropriate in vitro or in vivo model systems, including cultured human cells, genetically engineered mice, and lower organisms such as Drosophila and Dictyostelium.
4. Exploration of the potential for rational therapies, including genetic therapies.

We are currently searching for susceptibility and modifier genes in autism, Parkinson's disease, and Huntington's disease. As part of the Developmental Genome Anatomy Project, we also identify genes at breakpoints of balanced translocations associated with developmental abnormality. Finally we are examining the mechanism of pathogenesis of genetic defects in autism, biotin-responsive basal ganglia disease, Huntington's disease, Parkinson's disease, and neurofibromatosis, and pursuing assays to identify genetic and chemical modifiers, with the ultimate goal of contributing to effective rational therapies.

Genetic modifiers of somatic expansion and clinical phenotypes in Huntington's disease reveal shared and tissue-specific effects.
Authors:
bioRxiv
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Identification of genetic modifiers of Huntington's disease somatic CAG repeat instability by in vivo CRISPR-Cas9 genome editing.
Authors:
bioRxiv
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Single nuclei RNA-seq reveals a medium spiny neuron glutamate excitotoxicity signature prior to the onset of neuronal death in an ovine Huntington's disease model.
Authors: Authors: Jiang A, You L, Handley RR, Hawkins V, Reid SJ, Jacobsen JC, Patassini S, Rudiger SR, Mclaughlan CJ, Kelly JM, Verma PJ, Bawden CS, Gusella JF, MacDonald ME, Waldvogel HJ, Faull RLM, Lehnert K, Snell RG.
Hum Mol Genet
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Posttranscriptional regulation of FAN1 by miR-124-3p at rs3512 underlies onset-delaying genetic modification in Huntington's disease.
Authors: Authors: Kim KH, Hong EP, Lee Y, McLean ZL, Elezi E, Lee R, Kwak S, McAllister B, Massey TH, Lobanov S, Holmans P, Orth M, Ciosi M, Monckton DG, Long JD, Lucente D, Wheeler VC, MacDonald ME, Gusella JF, Lee JM.
Proc Natl Acad Sci U S A
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Splice modulators target PMS1 to reduce somatic expansion of the Huntington's disease-associated CAG repeat.
Authors: Authors: McLean ZL, Gao D, Correia K, Roy JCL, Shibata S, Farnum IN, Valdepenas-Mellor Z, Kovalenko M, Rapuru M, Morini E, Ruliera J, Gillis T, Lucente D, Kleinstiver BP, Lee JM, MacDonald ME, Wheeler VC, Mouro Pinto R, Gusella JF.
Nat Commun
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Tissue- and cell-type-specific molecular and functional signatures of 16p11.2 reciprocal genomic disorder across mouse brain and human neuronal models.
Authors: Authors: Tai DJC, Razaz P, Erdin S, Gao D, Wang J, Nuttle X, de Esch CE, Collins RL, Currall BB, O'Keefe K, Burt ND, Yadav R, Wang L, Mohajeri K, Aneichyk T, Ragavendran A, Stortchevoi A, Morini E, Ma W, Lucente D, Hastie A, Kelleher RJ, Perlis RH, Talkowski ME, Gusella JF.
Am J Hum Genet
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Parallelized engineering of mutational models using piggyBac transposon delivery of CRISPR libraries.
Authors: Authors: Nuttle X, Burt ND, Currall B, Moysés-Oliveira M, Mohajeri K, Bhavsar R, Lucente D, Yadav R, Tai DJC, Gusella JF, Talkowski ME.
Cell Rep Methods
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Modification of Huntington's disease by short tandem repeats.
Authors: Authors: Hong EP, Ramos EM, Aziz NA, Massey TH, McAllister B, Lobanov S, Jones L, Holmans P, Kwak S, Orth M, Ciosi M, Lomeikaite V, Monckton DG, Long JD, Lucente D, Wheeler VC, Gillis T, MacDonald ME, Sequeiros J, Gusella JF, Lee JM.
Brain Commun
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PMS1 as a target for splice modulation to prevent somatic CAG repeat expansion in Huntington's disease.
Authors: Authors: McLean ZL, Gao D, Correia K, Roy JCL, Shibata S, Farnum IN, Valdepenas-Mellor Z, Rapuru M, Morini E, Ruliera J, Gillis T, Lucente D, Kleinstiver BP, Lee JM, MacDonald ME, Wheeler VC, Pinto RM, Gusella JF.
bioRxiv
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A Cdk5-derived peptide inhibits Cdk5/p25 activity and improves neurodegenerative phenotypes.
Authors: Authors: Pao PC, Seo J, Lee A, Kritskiy O, Patnaik D, Penney J, Raju RM, Geigenmuller U, Silva MC, Lucente DE, Gusella JF, Dickerson BC, Loon A, Yu MX, Bula M, Yu M, Haggarty SJ, Tsai LH.
Proc Natl Acad Sci U S A
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