TorsinA restoration in a mouse model identifies a critical therapeutic window for DYT1 dystonia

Abstract

In inherited neurodevelopmental diseases, pathogenic processes unique to critical periods during early brain development may preclude effectiveness of gene modification therapies applied later in life. We explored this question in a mouse model of DYT1 dystonia, a neurodevelopmental disease caused by a loss-of-function mutation in the TOR1A gene encoding torsinA. To define the temporal requirements for torsinA in normal motor function and gene replacement therapy, we developed a mouse line enabling spatiotemporal control of the endogenous torsinA allele. Suppressing torsinA during embryogenesis caused dystonia-mimicking behavioral and neuropathological phenotypes. Suppressing torsinA during adulthood, however, elicited no discernible abnormalities, establishing an essential requirement for torsinA during a developmental critical period. The developing CNS exhibited a parallel "therapeutic critical period" for torsinA repletion. While restoring torsinA in juvenile DYT1 mice rescued motor phenotypes, there was no benefit from adult torsinA repletion. These data establish a unique requirement for torsinA in the developing nervous system and demonstrate that the critical period genetic insult provokes permanent pathophysiology mechanistically delinked from torsinA function. These findings imply that to be effective, torsinA-based therapeutic strategies must be employed early in the course of DYT1 dystonia.

Striatal Cholinergic Dysregulation after Neonatal Decrease in X‐Linked Dystonia Parkinsonism‐Related TAF1 Isoforms

“…Appearance of symptoms in XDP may result from a delayed manifestation of TAF1 ‐induced dysfunction in early development or a consequence of TAF1 dysfunction only in the adult brain. As in other diseases, including other forms of dystonia, this distinction has very important implications for the timing of therapeutic interventions 39,40 . Thus, we asked if the downregulation of cTaf1 and nTaf1 transcripts at a later stage in maturation leads to the same consequences as in the newborn.…”

“…As in other diseases, including other forms of dystonia, this distinction has very important implications for the timing of therapeutic interventions. 39,40 Thus, we asked if the downregulation of cTaf1 and nTaf1 transcripts at a later stage in maturation leads to the same consequences as in the newborn. In the only in vivo use of the C-TAF1 miRNA vector, we performed bilateral striatal injections of the C-TAF1, N-TAF1, C/N-TAF1, and scramble control miRNA AAV1 GFP viruses in 3-week-old rats and assayed motor function before and 3 months after surgery (Fig.…”

From the Matrix to the Nucleus and Back: Mechanobiology in the Light of Health, Pathologies, and Regeneration of Oral Periodontal Tissues

“…Reduction in the function of the ATPase associated with diverse cellular activities (AAA+ ATPase) TorsinA or rather its Caenorhabditis elegans ortholog OOC-5 have been shown to rescue the Lamin mutation phenotype [233]. This is interesting, as TorsinA normally enhances NMT through LINC regulation, and mutations in the gene are associated with dystonia and joint contracture [234,235]. Thus, in the presence of a mutated and, therefore, dysfunctional Lamin, an additional decrease in TorsinA activity with concomitant reduction in NMT prevents nuclear damage.…”

Teaching an Old Drug a New Trick for Dystonia

“…This long-duration benefit is an important finding, since a therapeutic critical period for restoring TorsinA function likely exists in humans. 2 Ritonavir appears to exert these effects in a mechanism distinct from its known target, HIV-1 protease. Instead, molecular assays suggest a role for its modulation of eukaryotic translation initiation factor 2 subunit α (eIF2α), a key component of the endoplasmic reticular-integrated stress response that may be a generalizable mechanism for dystonia.…”

“…Going further, administration of ritonavir in the perinatal period produced long‐lasting normalization of structural abnormalities as assessed by diffusion tensor magnetic resonance imaging. This long‐duration benefit is an important finding, since a therapeutic critical period for restoring TorsinA function likely exists in humans 2 …”