Identifier Results
| Field | Value |
|---|---|
| Identifier | nemo:dat-ztfn3cc |
| Dataset Name | Long somatic DNA-repeat expansion drives neurodegeneration in Huntington disease |
| Version | NA |
| Release Date | NA |
| DOI | NA |
| Source Data URL | NA |
| Dataset Collection URL | NA |
| Description | Huntington Disease (HD) is a fatal genetic disease in which most of a person’s striatal projection neurons (SPNs) degenerate and die. The central biological question about HD has involved how the disease-causing inherited DNA repeat (CAGn) in the huntingtin (HTT) gene leads to neurodegeneration after a long latent period. The length of the HTT CAG repeat varies within the brain (somatic mosaicism), and many common human-genetic modifiers of HD age-at-onset are in genes that affect DNA-repeat stability. To understand how the HTT CAG repeat might underlie pathological changes in HD, we developed a method to sequence and measure the CAG repeat together with genome-wide RNA expression in the same cells. We found that the CAG repeat routinely expands from 40-45 CAGs (germline) to 100-500+ CAGs in SPNs but not in other striatal cell types, with these long expansions acquired asynchronously by individual SPNs. Surprisingly, somatic expansion from 40 to 150 CAGs had no apparent direct effect upon SPN gene expression. In contrast, sparse SPNs with 150-500+ CAGs had profound gene-expression changes – affecting hundreds of genes, escalating with further repeat expansion, eroding positive and then negative features of SPN identity, and culminating in expression of senescence/apoptosis genes. Across stages of HD, these “SLEAT” SPNs (with somatic long expansions and asynchronous toxicity) appeared in proportion to rates of SPN loss. Our experiments, analyses and simulations suggest that individual SPNs undergo decades of biologically quiet DNA-repeat expansion to a high threshold length, then asynchronously pass through a brief toxicity phase before dying. We conclude that, at any moment in the course of HD, most SPNs have an innocuous (but unstable) huntingtin gene, and that HD pathogenesis is a DNA process for almost all of a neuron’s life. |
| Keywords | human, caudate, cortex, Huntington's |
| Total Files in Collection | 0 |
| Total Size in Collection (in GB) | 0.0 |
| Authors | Robert E. Handsaker, Seva Kashin, Nora M. Reed, Steven Tan, Won-Seok Lee, Tara M. McDonald, Kiely Morris, Nolan Kamitaki, Christopher D. Mullally, Neda R. Morakabati, Melissa Goldman, Gabriel Lind, Rhea Kohli, Elisabeth Lawton, Marina Hogan, Kiku Ichihara, Sabina Berretta, Steven A. McCarroll |
| Organization | Stanley Center for Psychiatric Research, Broad Institute of MIT and Harvard, Cambridge, MA; Department of Genetics, Harvard Medical School, Boston, MA; Program in Neuroscience, Harvard Medical School, Boston, MA; McLean Hospital, Belmont, MA; Department of Psychiatry, Harvard Medical School, Boston, MA |
| Contact Person | Melissa Goldman |
| Contact E-Mail | mgoldman@broadinstitute.org |
| External Identifier | NA |
| Grant Name | CHDI Foundation (A-15608) the Harvard Medical School Department of Genetics, and the Harvard Ludwig Initiative in Neurodegenerative Disease |
| Consortium | NA |
| Data Repository | NeMO |
| Data Repository RRID | RRID:SCR_016152 |
| Data License | NA |
| Data Access | NA |
| Community Standards | NA |
| Study Organism | human |
| Protocol ID | dx.doi.org/10.17504/protocols.io.4r3l22e3xl1y/v1; dx.doi.org/10.17504/protocols.io.36wgq3bmxlk5/v1 |
This identifier does not have sub-identifiers with "raw" data associated
This identifier does not have sub-identifiers with "analysis" data associated