Forebrain knock-out of torsinA reduces striatal free-water and impairs whole-brain functional connectivity in a symptomatic mouse model of DYT1 dystonia

Abstract

Multiple lines of evidence implicate striatal dysfunction in the pathogenesis of dystonia, including in DYT1, a common inherited form of the disease. The impact of striatal dysfunction on connected motor circuits and their interaction with other brain regions is poorly understood. Conditional knock-out (cKO) of the DYT1 protein torsinA from forebrain cholinergic and GABA-ergic neurons creates a symptomatic model that recapitulates many characteristics of DYT1 dystonia, including the developmental onset of overt twisting movements that are responsive to anti-muscarinic drugs. We performed diffusion MRI and resting-state functional MRI on cKO mice of either sex to define abnormalities of diffusivity and functional connectivity in cortical, subcortical, and cerebellar networks. The striatum was the only region to exhibit an abnormality of diffusivity, indicating a selective microstructural deficit in cKO mice. The striatum of cKO mice exhibited widespread increases in functional connectivity with somatosensory cortex, thalamus, vermis, cerebellar cortex and nuclei, and brainstem. The current study provides the first in vivo support that direct pathological insult to forebrain torsinA in a symptomatic mouse model of DYT1 dystonia can engage genetically normal hindbrain regions into an aberrant connectivity network. These findings have important implications for the assignment of a causative region in CNS disease.

Neuroimaging Applications in Dystonia

“…Corroborating these findings, an ex vivo study in the heterozygous DYT1 knock-in mouse model showed reduced connectivity of the cerebello-thalamic, thalamo-cortical and thalamo-striatal pathways in mutants compared to wild type (Ulug et al, 2011). Another study reported deficits of free water diffusivity and widespread increases in functional connectivity of the stratum with somatosensory cortex, thalamus, cerebellum and brainstem in the conditional knock-out mice of the DYT1 protein torsinA (DeSimone et al, 2017). As the cerebello-thalamo-cortical pathway facilitates intracortical inhibition via projections to interneurons in the sensorimotor cortex (Molinari, Filippini, & Leggio, 2002), these findings may suggest the presence of the intermediary pattern in non-manifesting carriers that may act as a buffer against the aberrant outflow from the proximal part of this pathway (Niethammer, Carbon, Argyelan, & Eidelberg, 2011).…”

Whole exome sequencing identifies novel DYT1 dystonia-associated genome variants as potential disease modifiers

“…The loss of torsinA function in either the cerebral cortex or cerebellum result in motor dysfunction (DeSimone et al, 2017; Fremont, Tewari, Angueyra, & Khodakhah, 2017; Yokoi, Dang, Mitsui, Li, & Li, 2008), indicating a neuronal component of TOR1A’s function in dystonia. Based on these observations, we examined the 195 genes that carry candidate ΔE mutation modifiers for their association with neuropsychiatric and neuromuscular disorders.…”

The Role of Torsin AAA+ Proteins in Preserving Nuclear Envelope Integrity and Safeguarding Against Disease

“…Thus, the differential expression pattern of Torsins likely contributes to the tissue-specific manifestation of TorsinA∆E-linked pathology. Indeed, phenotypes similar to DYT1 dystonia-specific symptoms were observed in conditional mouse models upon deletion of TorsinA in individual brain regions [47][48][49]. These symptoms manifest as abnormal posturing and dystonia-like twisting motions, as well as neurodegeneration of select regions of the central nervous system.…”

“…In addition, TorsinA deletion or depletion causes dystonic symptoms even in animal models that do not express TorsinA∆E [47,49,53]. In fact, a mildly beneficial effect of expressing TorsinA∆E relative to a Torsin deletion was observed both in animal models [47,48] and tissue culture models [30], suggesting that TorsinA∆E may act as a hypomorphic allele.…”