| First Author | Rittiner JE | Year | 2016 |
| Journal | Neuron | Volume | 92 |
| Issue | 6 | Pages | 1238-1251 |
| PubMed ID | 27939583 | Mgi Jnum | J:325327 |
| Mgi Id | MGI:6835385 | Doi | 10.1016/j.neuron.2016.11.012 |
| Citation | Rittiner JE, et al. (2016) Functional Genomic Analyses of Mendelian and Sporadic Disease Identify Impaired eIF2alpha Signaling as a Generalizable Mechanism for Dystonia. Neuron 92(6):1238-1251 |
| abstractText | Dystonia is a brain disorder causing involuntary, often painful movements. Apart from a role for dopamine deficiency in some forms, the cellular mechanisms underlying most dystonias are currently unknown. Here, we discover a role for deficient eIF2alpha signaling in DYT1 dystonia, a rare inherited generalized form, through a genome-wide RNAi screen. Subsequent experiments including patient-derived cells and a mouse model support both a pathogenic role and therapeutic potential for eIF2alpha pathway perturbations. We further find genetic and functional evidence supporting similar pathway impairment in patients with sporadic cervical dystonia, due to rare coding variation in the eIF2alpha effector ATF4. Considering also that another dystonia, DYT16, involves a gene upstream of the eIF2alpha pathway, these results mechanistically link multiple forms of dystonia and put forth a new overall cellular mechanism for dystonia pathogenesis, impairment of eIF2alpha signaling, a pathway known for its roles in cellular stress responses and synaptic plasticity. |
