Limited regional cerebellar dysfunction induces focal dystonia in mice

Raike, Robert S.; Pizoli, Carolyn; Weisz, Catherine; Maagdenberg, Arn M. J. M. van den; Jinnah, H. A.; Hess, Ellen J.

doi:10.1016/j.nbd.2012.07.019

Cited by 68 publications

(81 citation statements)

References 55 publications

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“…We have previously shown that restricting the tottering mouse genotype to PCs causes ataxia and episodic dystonia, similar to the phenotype observed in tottering mice (Raike et al, 2012). Additionally, selective postnatal knockdown of Cacna1a in PCs using L7-Cre also caused overt motor defects.…”

Section: Discussionsupporting

confidence: 66%

“…Though Cacna1a is most abundantly expressed in cerebellum, other brain regions relevant for movement such as motor cortex and basal ganglia show expression as well (Lein et al, 2007). This scenario cannot be ruled out, but is not supported by data from other Cacna1a mutants where cerebellar circuitry is specifically implicated in behavioral dysfunction (Campbell et al, 1999, Walter et al, 2006, Raike et al, 2012). Fourth, the dysfunctional signaling occurs downstream of GCs and PCs in deep cerebellar nuclei, which also express Ca V 2.1 channels.…”

Section: Discussionmentioning

confidence: 93%

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The first knockin mouse model of episodic ataxia type 2

Rose

Kriener

Heinzer

et al. 2014

Experimental Neurology

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Episodic ataxia type 2 (EA2) is an autosomal dominant disorder associated with attacks of ataxia that are typically precipitated by stress, ethanol, caffeine or exercise. EA2 is caused by loss-of-function mutations in the CACNA1A gene, which encodes the α1A subunit of the CaV2.1 voltage-gated Ca2+ channel. To better understand the pathomechanisms of this disorder in vivo, we created the first genetic animal model of EA2 by engineering a mouse line carrying the EA2-causing c.4486T>G (p.F1406C) missense mutation in the orthologous mouse Cacna1a gene. Mice homozygous for the mutated allele exhibit a ∼70% reduction in CaV2.1 current density in Purkinje cells, though surprisingly do not exhibit an overt motor phenotype. Mice hemizygous for the knockin allele (EA2/− mice) did exhibit motor dysfunction measurable by rotarod and pole test. Studies using Cre-flox conditional genetics explored the role of cerebellar Purkinje cells or cerebellar granule cells in the poor motor performance of EA2/− mice and demonstrate that manipulation of either cell type alone did not cause poor motor performance. Thus, it is possible that subtle dysfunction arising from multiple cell types is necessary for the expression of certain ataxia syndromes.

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Section: Discussionsupporting

confidence: 66%

Section: Discussionmentioning

confidence: 93%

The first knockin mouse model of episodic ataxia type 2

Rose

Kriener

Heinzer

et al. 2014

Experimental Neurology

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“…Clinical and experimental studies of secondary dystonia strongly implicate forebrain dysfunction as a cause of dystonia (49,50), but several hindbrain elements have also been implicated (51)(52)(53)(54). Taking advantage of different Cre-expressing lines, we began to explore which brain regions are sufficient to mimic the behavioral abnormalities of N-SKI mice.…”

Section: Histology and Immunohistochemistrymentioning

confidence: 99%

TorsinA hypofunction causes abnormal twisting movements and sensorimotor circuit neurodegeneration

et al. 2014

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Lack of a preclinical model of primary dystonia that exhibits dystonic-like twisting movements has stymied identification of the cellular and molecular underpinnings of the disease. The classical familial form of primary dystonia is caused by the DYT1 (ΔE) mutation in TOR1A, which encodes torsinA, AAA + ATPase resident in the lumen of the endoplasmic reticular/nuclear envelope. Here, we found that conditional deletion of Tor1a in the CNS (nestin-Cre Tor1a flox/-) or isolated CNS expression of DYT1 mutant torsinA (nestin-Cre Tor1a flox/ΔE ) causes striking abnormal twisting movements. These animals developed perinuclear accumulation of ubiquitin and the E3 ubiquitin ligase HRD1 in discrete sensorimotor regions, followed by neurodegeneration that was substantially milder in nestin-Cre Tor1a flox/ΔE compared with nestin-Cre Tor1a flox/-animals. Similar to the neurodevelopmental onset of DYT1 dystonia in humans, the behavioral and histopathological abnormalities emerged and became fixed during CNS maturation in the murine models. Our results establish a genetic model of primary dystonia that is overtly symptomatic, and link torsinA hypofunction to neurodegeneration and abnormal twisting movements. These findings provide a cellular and molecular framework for how impaired torsinA function selectively disrupts neural circuits and raise the possibility that discrete foci of neurodegeneration may contribute to the pathogenesis of DYT1 dystonia. IntroductionThe primary dystonias, a group of sporadic and inherited illnesses, are a striking example of selective vulnerability of CNS sensorimotor circuits (1, 2). Dystonia -defined as prolonged, involuntary twisting movements -is traditionally classified as "primary" if it occurs in isolation and in the absence of neuropathological change. In contrast, "secondary" dystonic movements occur consequent to CNS damage (e.g., from stroke, trauma, or neurodegeneration), and are typically accompanied by additional neurological signs and symptoms. This classification scheme has been criticized (3), however, because neuroimaging of patients with primary dystonia indicates the presence of subtle neuropathological changes, and few primary dystonia brains have been comprehensively analyzed (4). Indeed, despite considerable interest in the pathophysiology of primary dystonia, the molecular and cellular underpinnings of CNS dysfunction and the identity of affected motor structures and cell types remain poorly understood. DYT1 dystonia is a common inherited form of primary dystonia that typically manifests during a discrete period of childhood, implicating abnormal development as the cause of motor dysfunction. This neurodevelopmental disease is caused by a 3 bp in-frame mutation in TOR1A that removes a single glutamic acid residue (ΔE) from the torsinA protein. TorsinA is a ubiquitously expressed AAA + protein residing in the lumen of the ER/nuclear envelope (ER/NE) space (5-7). Accumulating evidence indicates that the DYT1 mutation acts by impairing torsinA function through multiple mechan...

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“…Motor behavioral effects of different stimulation parameters were also assessed using a semi-quantitative scoring system adapted from prior nonhuman primate, porcine and rodent studies [30][31][32][33][34]. Prior to these experiments, the maximal tolerable stimulation amplitude was determined for each DBS lead contact for each animal by a consensus of the veterinary and scientist team.…”

Section: Motor Behavior Assessmentsmentioning

confidence: 99%