Purkinje cell dysfunction and loss in a knock-in mouse model of Huntington Disease

Dougherty, Sarah; Reeves, John L.; Lesort, Mathieu; Detloff, Peter J.; Cowell, Rita M.

doi:10.1016/j.expneurol.2012.11.015

Cited by 35 publications

(30 citation statements)

References 47 publications

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“…It should be noted that there are no Huntington inclusions in the Purkinje neurons until 12 weeks [28]. Similar results were obtained using the HdhQ200 knockin mouse model of Huntington’s disease, with loose patch recordings of Purkinje neurons showing a reduction in firing rate in the Huntington’s disease mice compared with control littermates [29]. …”

Section: Altered Intrinsic Purkinje Neuron Pacemaking As a Primary Drsupporting

confidence: 60%

Translating Cerebellar Purkinje Neuron Physiology To Progress In Dominantly Inherited Ataxia

Chopra

Shakkottai

2014

Future Neurol.

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The cerebellum is an important structure for accurate control and timing of movement, and Purkinje neurons in the cerebellar cortex are key players in cerebellar motor control. Cerebellar dysfunction can result in ataxia, a disorder characterized by postural instability, gait disturbances and motor incoordination. Cerebellar ataxia is a symptom of a number of conditions, and the emerging evidence that Purkinje neuron dysfunction, in particular, abnormal Purkinje neuron repetitive firing, is a major driver of motor dysfunction in a subset of dominantly inherited ataxias is dicussed. Abnormalities in Purkinje neuron excitability that are observed in mouse models of each of these disorders, and where appropriate describe studies linking particular ion channels to aberrant excitability are also discussed. Common mechanisms of dysfunction and speculate about potential therapeutic targets, suggesting that Purkinje neuron firing abnormalities are a novel target for improving motor dysfunction in patients with some forms of dominantly inherited ataxia are proposed.

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Section: Altered Intrinsic Purkinje Neuron Pacemaking As a Primary Drsupporting

confidence: 60%

Translating Cerebellar Purkinje Neuron Physiology To Progress In Dominantly Inherited Ataxia

Chopra

Shakkottai

2014

Future Neurol.

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“…However, SHH and FGF8 were added after neuronal induction to generate these neurons. Cerebellar Purkinje neurons, which are known to have a crucial role in NPD 36 and HD 50,51 , appeared in our culture between 45–48 days, which is relatively longer and is a similar pattern as that observed in the developing cerebellum in vivo 29,30 . Thus, our method can rapidly generate subtype-specific or region-specific neurons compared to the other currently available neurodifferentiation methods 10,11,21,22 .…”

Section: Discussionsupporting

confidence: 67%

Rapid generation of sub-type, region-specific neurons and neural networks from human pluripotent stem cell-derived neurospheres

et al. 2015

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Stem cell-based neuronal differentiation has provided a unique opportunity for disease modeling and regenerative medicine. Neurospheres are the most commonly used neuroprogenitors for neuronal differentiation, but they often clump in culture, which has always represented a challenge for neurodifferentiation. In this study, we report a novel method and defined culture conditions for generating sub-type or region-specific neurons from human embryonic and induced pluripotent stem cells derived neurosphere without any genetic manipulation. Round and bright-edged neurospheres were generated in supplemented knockout serum replacement medium (SKSRM) with 10% CO2, which doubled the expression of the NESTIN, PAX6 and FOXG1 genes compared to those cultured with 5% CO2. Furthermore, an additional step (AdSTEP) was introduced to fragment the neurospheres and facilitate the formation of a neuroepithelial-type monolayer that we termed the “neurosphederm”. The large neural tube-type rosette (NTTR) structure formed from the neurosphederm, and the NTTR expressed higher levels of the PAX6, SOX2 and NESTIN genes compared to the neuroectoderm-derived neuroprogenitors. Different layers of cortical, pyramidal, GABAergic, glutamatergic, cholinergic neurons appeared within 27 days using the neurosphederm, which is a shorter period than in traditional neurodifferentiation-protocols (42–60 days). With additional supplements and timeline dopaminergic and Purkinje neurons were also generated in culture too. Furthermore, our in vivo results indicated that the fragmented neurospheres facilitated significantly better neurogenesis in severe combined immunodeficiency (SCID) mouse brains compared to the non-fragmented neurospheres. Therefore, this neurosphere-based neurodifferentiation protocol is a valuable tool for studies of neurodifferentiation, neuronal transplantation and high throughput screening assays.

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“…As shown in our case, abnormal protein accumulation was usually found to be in the nucleus and cytoplasm of Purkinje cell [5]. Mice model of Huntington's disease revealed Purkinje cell death and dysfunction of the neurons in addition to accumulation of the mutant huntingtin within the Purkinje cells [6]. Not only Purkinje cell loss, but nerve cell damages of the fastigal, globose, emboliform, and dentate nuclei were reported in autopsy cases of Huntington's disease [5].…”

Section: Case Reportsupporting

confidence: 69%

Case Study: Somatic Sprouts and Halo-Like Amorphous Materials of the Purkinje Cells in Huntington’s Disease

et al. 2015

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We described a 63-year-old Japanese female with genetically confirmed Huntington's disease who showed unusual pathological findings in the cerebellum. This case exhibited typical neuropathological features as Huntington's disease, including severe degeneration of the neostriatum and widespread occurrence of ubiquitin and expanded polyglutamine-positive neuronal intranuclear and intracytoplasmic inclusions. The cerebellum was macroscopically unremarkable; however, somatic sprouts and halo-like amorphous materials of Purkinje cell with a large amount of torpedoes were noteworthy.Furthermore, the Purkinje cells were found to have granular cytoplasmic inclusions.

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Purkinje cell dysfunction and loss in a knock-in mouse model of Huntington Disease

Cited by 35 publications

References 47 publications

Translating Cerebellar Purkinje Neuron Physiology To Progress In Dominantly Inherited Ataxia

Translating Cerebellar Purkinje Neuron Physiology To Progress In Dominantly Inherited Ataxia

Rapid generation of sub-type, region-specific neurons and neural networks from human pluripotent stem cell-derived neurospheres

Case Study: Somatic Sprouts and Halo-Like Amorphous Materials of the Purkinje Cells in Huntington’s Disease

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