Cell-specific translational profiling in Huntington's Disease mouse models

Weill Medical Coll Of Cornell Univ, New York NY

Investigators

Linked publications & trials

Abstract

DESCRIPTION (provided by applicant): Huntington's Disease (HD) has been linked to an expansion of CAG repeats in the huntingtin (htt) gene. A central mystery of the disease is that medium spiny neurons (MSNs) of the striatum die selectively, despite ubiquitous expression of the CAG- expanded mutant huntingtin (mhtt) gene in the nervous system. The basis for this selective vulnerability is unknown, but presents a prime target for therapeutic intervention. Among striatal MSNs, the distinct population of striatopallidal neurons, which project to the globus pallidum externa, express dopamine D2 receptors (Drd2s) and inhibit voluntary movement, dies before striatonigral neurons, which project to the substantia nigra pars reticulata, express dopamine D1 receptors (Drd1s) and stimulate voluntary motion. This selective cell death may explain the clinical presentation of HD, which begins with characteristic uncontrolled movements ("chorea") and progresses to a Parkinsonian hypokinesis in the later stages. Many HD mouse models have been developed that recapitulate features of the human disease, but technical limitations have prevented the study of differences between striatonigral and striatopallidal populations in these models. Although these mouse models share a similar basic circuitry within the striatum to humans, it has not been possible to separate the neuronal populations for analysis, because they are anatomically intermixed and morphologically indistinguishable. A new technology developed in collaboration between the Heintz and Greengard labs, called translating ribosome affinity purification, "TRAP", will allow the investigation of changes in the vulnerable striatopallidal neurons for the first time. This technology uses GFP-tagged ribosomal proteins to isolate translated mRNA pools from genetically defined cell populations, eliminating the need to disassociate the neuronal populations before analysis. After isolation, the mRNA profile can be analyzed using microarrays, allowing identification of targets that contribute to selective vulnerability. Using this technique, we have identified the sphingosine-1-phosphate pathway as a potential mediator of selective vulnerability.