|
Mechanism of biotin-responsive basal ganglia disease – Gusella
Biotin-responsive basal ganglia disease (BBGD) is an inherited childhood disorder featuring cogwheel rigidity, dystonia, quadriparesis, necrosis in the head of the caudate, that is fatal, if left untreated. Symptoms disappear within a few days with the administration of high doses of biotin. With investigators from Saudi Arabia’s King Faisal Specialist Hospital and Research Centre, the Gusella group has recently identified the cause of BBGD as missense mutations in a putative transporter gene, SLC19A3, and is generating cell and animal models of this disorder, as well as identification of additional patients worldwide for genotype-phenotype analysis.
Mechanism of aberrant IKBKAP splicing in familial dysautonomia – Slaugenhaupt
Familial Dysautonomia is a hereditary sensory and autonomic neuropathy caused by mutations in the IKBKAP gene. The major mutation causes aberrant mRNA splicing, and previous studies in the Slaugenhaupt lab have shown that the level of exon skipping, and therefore the amount of normal IKAP protein, varies in a tissue specific manner. With Dr. Robin Reed at Harvard Medical School, the lab has developed both in vitro and in vivo splicing systems in order to determine how this mutation alters splicing, with the goal of developing therapies based on splicing modification.
Development of a mouse model for familial dysautonomia – Slaugenhaupt
The Slaugenhaupt lab has created both an Ikbkap knockout mouse in collaboration with Dr. Jim Pickel at NIMH, as well as transgenic mouse lines using a human BAC following insertion of the FD splicing mutation. Characterization of these lines will shed light on the crucial role of IKAP in neuronal development, as well as provide a means for examining tissue-specific alternative splicing. Further, the mice that result from crossing these lines will likely represent the most complete and accurate model of human FD.
Alternative Splicing as a mechanism for specifying unique cellular identity – Chess
The Drosophila Dscam (Down syndrome cell adhesion molecule) gene is essential for axon guidance and has over 38,000 possible alternative splice forms. We have showed that each individual cell’s Dscam repertoire is different from those of its neighbors, providing a potential mechanism for the generation of unique cell identity in the nervous system and elsewhere. We are also investigating mammalian genes whose alterative splicing might be used to similarly generate diversity.
Normal function of huntingtin, the protein product of the Huntington’s disease gene – MacDonald
HD neurodegeneration is due to a dominantly acting polyglutamine expansion that acts via its context in the huntingtin protein to cause preferential vulnerability of striatal neurons. To understand the normal function of huntingtin that could contribute to this specificity, the MacDonald lab is pursuing identification of proteins in huntingtin complexes and studies to unmask huntingtin’s essential activities in embryonic development, particularly gastrulation and mid-gestation phenotypes produced by huntingtin deficiency in the mouse.
Huntington’s disease repeat instability and pathogenesis – Wheeler
This project uses accurate genetic knock-in mouse models of Huntington’s disease (HD) to investigate the role of the mismatch repair pathway in CAG repeat instability and in early stages of HD pathogenesis. Genes found to modify pathogenesis in the mouse are then used as candidates to test as modifiers in HD patient populations in genetic association studies.
Mechanism of the Huntington’s disease mutation – MacDonald
To define essential steps in the HD disease process, the MacDonald lab studies Hdh CAG knock-in mice and striatal cell lines that are precise genetic replicas of adult onset and juvenile onset HD CAG mutations. Phenotyping of such mice has uncovered a cascade of presymptomatic disease events that manifest before overt neuropathology. Knowledge of very early presymptomatic disease changes provides candidate pathways that may lead to biomarkers in studies with at risk individuals and phenotypes that can spark the development of strategies to slow the disease process, rather than the disease symptoms.
Role of Neurofibromatosis 2 (NF2) protein merlin in cell signaling to the actin cytoskeleton – James, Ramesh
This project aims to understand merlin’s role in cell signaling, which might enable us to understand how merlin functions as a tumor suppressor, and how its absence results in meningiomas and schwannomas in NF2 patients.
Role of novel merlin interactor magicin – Ramesh
Our work is focused on understanding how magicin signals from the cytoskeleton to the nucleus. Our results also indicate that magicin might play an important role in transcription regulation and gene expression, which could be important for many pathological conditions including cancer.
Understanding NF2 tumor suppressor function in human meningioma cell culture model systems – James
In collaboration with members of the MGH Departments of Neurology and Pathology, Dr. James has established primary human merlin-deficient meningioma cell cultures, together with patient-matched arachnoidal cells, the normal cell counterpart from which meningiomas derive. Defining differences between these cell types will provide clues to merlin’s role as a tumor suppressor. Additionally, gene expression profiling of merlin-knockdown RNAi-treated arachnoidal cells is being employed to reveal genes and pathways regulated by merlin in these cells.
Functional characterization of the CLN3 and CLN6-encoded proteins, battenin and linclin – Cotman, MacDonald
The proteins encoded by the CLN3 and CLN6 genes, which are mutated in two forms of NCL, are novel transmembrane proteins localized to the endosomal/lysosomal membrane (battenin) and endoplasmic reticulum-mitochondrial membrane (linclin), respectively, but the function of these proteins is yet to be discovered. We are studying battenin and linclin function by identifying the protein complexes in which they participate, and by cellular and biochemical studies of membrane trafficking and vesicle fusion.
Chemical genetic modifier approach to unraveling the cellular pathways involved in JNCL (CLN3) and vLINCL (CLN6) – Cotman
Dr. Cotman’s laboratory is utilizing chemical genetic approaches to identify modifiers of juvenile NCL and late-infantile NCL. In collaboration with investigators at the Broad Institute of Harvard and MIT, small molecule perturbagens are being tested for their ability to modify biochemical and cellular phenotypes in cerebellar cell lines harboring the JNCL and vLINCL mutations.
Studies of genes subject to monoallelic expression – Chess
The Chess lab has played a central role in defining a class of autosomal genes with properties similar to X-inactivation. Taking advantage of the fact that monoallelically expressed genes replicate asynchronously, they discovered that the replication timing of these genes is coordinated at a whole-chromosome level. Thus, there is a randomly determined non-equivalence between the maternal and paternal copy of each autosome. The Chess group uses molecular biology, microarray technology and informatics to dissect underlying mechanisms of monoallelic expression and chromosome-pair non-equivalence.
Mechanism of mucolipidosis type IV – Slaugenhaupt
MLIV is a lysosomal storage disorder that is characterized by severe neurologic and ophthalmologic abnormalities due to defective transport of membrane components in the late endosomal/lysosomal pathway. The mutant gene, MCOLN1, encodes a novel transmembrane protein, mucolipin-1, that shows homology to the transient receptor potential (TRP) gene superfamily and functions as a calcium permeable channel that is transiently modulated by changes in calcium concentration. The Slaugenhaupt lab is pursuing generation of cell and mouse models of this disorder.
Investigation of normal function of human disease gene orthologues in Drosophila – Gusella, Ito
In many instances, identification of genetic genes associated with human disease reveals a mutation that affects a protein whose function is not known. Drosophila melanogaster, the fruit-fly, offers a potential alternative for investigating such genes, with powerful genetic techniques to investigate structure-function relationships and functional interactions. We are using this system to explore the normal functions of the fly orthologues of huntingtin, the protein implicated in Huntington’s disease, torsinA, the protein altered in early-onset torsion dystonia, IKAP, the protein inactivated in familial dysautonomia and tuberin and hamartin, the Tuberous Sclerosis complex proteins.
Functions of Tuberous Sclerosis Complex (TSC) proteins, tuberin and hamartin in the CNS – Ramesh
This project aims to understand how Tuberous Sclerosis Complex (TSC) proteins could play a role in distinct signaling in the CNS, which could provide a better understanding of the neurological manifestations such as seizures, mental retardation and autism associated with the disorder.
Role of Pam in synapse formation and growth – Ramesh
Our goal is to understand using cellular and mouse models whether Pam, a protein that we identified as a partner of the TSC proteins could play a key role in synaptic plasticity and in learning/memory by regulating the TSC proteins.
|
