The Lurcher mouse: Fresh insights from an old mutant

Vogel, Michael W.; Caston, J.; Yuzaki, Michisuke; Mariani, Jean

doi:10.1016/j.brainres.2005.11.086

Cited by 68 publications

(62 citation statements)

References 175 publications

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“…The overexpression or deletion of the apoptosis-related genes Bcl-2 or Bax, respectively, did not completely prevent the degeneration of Lc Purkinje cells (Vogel et al, 2006). In addition, apoptosis requires normal ATP levels, whereas the ATP levels were decreased in HEK293 cells expressing GluD2…”

Section: Lc-mediated Cell Deathmentioning

confidence: 95%

“…5; supplemental Fig. 2, available at www.jneurosci.org as supplemental material) and possibly in Lc Purkinje cells (Vogel et al, 2006). Therefore, apoptosis is unlikely to be the main mechanism for Lc-mediated Purkinje cell death.…”

Section: Lc-mediated Cell Deathmentioning

confidence: 99%

“…The lurcher (Lc) mouse is an autosomal semidominant mutant originally described five decades ago (Vogel et al, 2006). In heterozygous mice (Lc/ϩ), cerebellar Purkinje cells specifically start to degenerate in a cell-autonomous manner by postnatal day 8 (P8), and most die during the second postnatal week; other cell types are eventually affected by secondary mechanisms (Wetts and Herrup, 1982).…”

Section: Introductionmentioning

confidence: 99%

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Reevaluation of Neurodegeneration inlurcherMice: Constitutive Ion Fluxes Cause Cell Death with, Not by, Autophagy

Nishiyama¹,

Matsuda²,

Kakegawa³

et al. 2010

J. Neurosci.

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The lurcher (Lc) mice have served as a valuable model for neurodegeneration for decades. Although the responsible mutation was identified in genes encoding ␦2 glutamate receptors (GluD2s), which are predominantly expressed in cerebellar Purkinje cells, how the mutant receptor (GluD2 Lc ) triggers cell death has remained elusive. Here, taking advantage of recent knowledge about the domain structure of GluD2, we reinvestigated Lc-mediated cell death, focusing on the "autophagic cell death" hypothesis. Although autophagy and cell death were induced by the expression of GluD2Lc in heterologous cells and cultured neurons, they were blocked by the introduction of mutations in the channel pore domain of GluD2Lc or by removal of extracellular Na ϩ . In addition, although GluD2 Lc is reported to directly activate autophagy, mutant channels that are not associated with n-PIST (neuronal isoform of protein-interacting specifically with TC10)-Beclin1 still caused autophagy and cell death. Furthermore, cells expressing GluD2Lc showed decreased ATP levels and increased AMP-activated protein kinase (AMPK) activities in a manner dependent on extracellular Na ϩ . Thus, constitutive currents were likely necessary and sufficient to induce autophagy via AMPK activation, regardless of the n-PIST-Beclin1 pathway in vitro. Interestingly, the expression of dominant-negative AMPK suppressed GluD2 Lc -induced autophagy but did not prevent cell death in heterologous cells. Similarly, the disruption of Atg5, a gene crucial for autophagy, did not prevent but rather aggravated Purkinje-cell death in Lc mice. Furthermore, calpains were specifically activated in Lc Purkinje cells. Together, these results suggest that Lc-mediated cell death was not caused by autophagy but necrosis with autophagic features both in vivo and in vitro.

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Section: Lc-mediated Cell Deathmentioning

confidence: 95%

Section: Lc-mediated Cell Deathmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

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Reevaluation of Neurodegeneration inlurcherMice: Constitutive Ion Fluxes Cause Cell Death with, Not by, Autophagy

Nishiyama¹,

Matsuda²,

Kakegawa³

et al. 2010

J. Neurosci.

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“…In addition to motor aspects of behavior, intact cerebellum function is necessary for cognition, including tests of spatial learning and classical conditioning (Lalonde and Strazielle 2003;Marien, Engelborghs, and DeDeyn 2001;Stanton 2000). A mutant mouse model (''Lurcher'' mouse), which displays loss of Purkinje cells, olivary neurons, and granule cells, shows alterations in cognitive function (exploration and spatial learning) and emotion, as well as motor skills (Vogel et al 2007). …”

Section: Cerebellarmentioning

confidence: 99%

Functional Assays for Neurotoxicity Testing

Moser

2010

Toxicol Pathol

127

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Neurobehavioral and pathological evaluations of the nervous system are complementary components of basic research and toxicity testing of pharmaceutical and environmental chemicals. While neuropathological assessments provide insight as to cellular changes in neurons, behavioral and physiological methods evaluate the functional consequences of disruption of neuronal communications. The underlying causes of certain behavioral alterations may be understood, but many do not have known direct associations with specific brain pathologies. In some cases, however, rapidly expanding mouse models (transgenic, knock-out) are providing considerable information on behavioral phenotypes of altered pathology. Behavior represents the integrated sum of activities mediated by the nervous system, and functional tests used for neurotoxicity testing tap different behavioral repertoires. These tests have an advantage over pathologic measures in that they permit repeated evaluation of a single animal over time to determine the onset, progression, duration, and reversibility of a neurotoxic injury. Functional assays range from a screening-level battery of tests to refined procedures to tap specific forms of learning and/or memory. This article reviews common procedures for behavioral toxicity testing and provides examples of chemical-specific neurobehavioral-pathological correlations in order to inform interpretation and integration of neuropathological and behavioral outcomes.

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“…The Lurcher (Lc) mouse is an autosomal semidominant mutant that displays the degeneration of virtually all of the cerebellar Purkinje cells (Vogel et al, 2007). In heterozygous mice (Lc/+), cerebellar Purkinje cells specifically start to degenerate in a cellautonomous manner by postnatal day 8 (P8), and most die during the second postnatal week.…”

Section: Spontaneously Occurring Ataxic Micementioning

confidence: 99%