From mice to men: lessons from mutant ataxic mice

Cendelín, Jan

doi:10.1186/2053-8871-1-4

Cited by 78 publications

(76 citation statements)

References 322 publications

(423 reference statements)

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“…They attracted the attention of the investigators not only as possible models of human ataxias (Cendelin, 2014), but also as invaluable tools to study the normal cerebellar development in times when genetic engineering was still in its infancy.…”

Section: Discussionmentioning

confidence: 99%

“…Although evidence supports the hypothesis that an absence of Reelin causes a loss of the CGCs and the PNs in the cerebellar cortex (Cendelin, 2014), very limited information is available on the occurrence and type of postnatal cell death in mutants. Our group has demonstrated that the CGCs of the Reeler mouse undergo apoptosis after TUNEL labeling of fragmented DNA, and that apoptosis in mutants is significantly higher than in normal wild-type (WT) littermates (Cocito et al, 2016).…”

Section: Introductionmentioning

confidence: 99%

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Cell death and neurodegeneration in the postnatal development of cerebellar vermis in normal and Reeler mice

Castagna

Merighi

2016

Annals of Anatomy - Anatomischer Anzeiger

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Section: Discussionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

Cell death and neurodegeneration in the postnatal development of cerebellar vermis in normal and Reeler mice

Castagna

Merighi

2016

Annals of Anatomy - Anatomischer Anzeiger

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“…The heterogeneous nature of the cerebellar ataxias combined with the unavailability of human brain tissue and the lack of reliable disease models have, however, hampered our understanding of the molecular disease mechanisms underlying cerebellar ataxias and thus, the development of effective therapies. Although mouse models of several cerebellar ataxias, including FRDA and SCAs, have provided valuable insights into the pathophysiology of these disorders (reviewed in 9 ), many questions remain about the observed species differences in disease phenotypes and the effectiveness of potential drugs in clinical trials. To help translate research from animal models into novel treatments for ataxia patients, it is essential to validate findings in the relevant affected human cell types, particularly in cerebellar Purkinje cells.…”

Section: Cerebellar Ataxiasmentioning

confidence: 99%

Recent advances in modelling of cerebellar ataxia using induced pluripotent stem cells

Wong

Watson

Becker

2017

J Neurol Neuromedicine

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The cerebellar ataxias are a group of incurable brain disorders that are caused primarily by the progressive dysfunction and degeneration of cerebellar Purkinje cells. The lack of reliable disease models for the heterogeneous ataxias has hindered the understanding of the underlying pathogenic mechanisms as well as the development of effective therapies for these devastating diseases. Recent advances in the field of induced pluripotent stem cell (iPSC) technology offer new possibilities to better understand and potentially reverse disease pathology. Given the neurodevelopmental phenotypes observed in several types of ataxias, iPSC-based models have the potential to provide significant insights into disease progression, as well as opportunities for the development of early intervention therapies. To date, however, very few studies have successfully used iPSC-derived cells to model cerebellar ataxias. In this review, we focus on recent breakthroughs in generating human iPSC-derived Purkinje cells. We also highlight the future challenges that will need to be addressed in order to fully exploit these models for the modelling of the molecular mechanisms underlying cerebellar ataxias and the development of effective therapeutics.

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“…The weaver homozygotes have been studied as an animal model of cerebellar disorders such as hereditary ataxias (Grüsser-Cornehls and Bäule 2001, Manto and Marmolino 2009, Cedelin 2014. GIRK2 is expressed, in the weaver cerebellum, from embryonic day 15 to postnatal day 20 (Wei et al 1997).…”

Section: Introductionmentioning

confidence: 99%

“…Cerebellar disorders such as ataxias are severe neurological conditions that comprise a wide spectrum of diseases characterized by motor incoordination, imbalance and degeneration of PCs (Grüsser-Cornehls and Bäule 2001, Manto and Marmolino 2009, Cedelin 2014). …”

Section: Introductionmentioning

confidence: 99%

Cerebellar cortex development in the weaver condition presents regional and age-dependent abnormalities without differences in Purkinje cells neurogenesis

Martí¹,

Santa-Cruz²,

Hervás³

et al. 2016

Acta Neurobiologiae Experimentalis

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Ataxias are neurological disorders associated with the degeneration of Purkinje cells (PCs). Homozygous weaver mice (wv/wv) have been proposed as a model for hereditary cerebellar ataxia because they present motor abnormalities and PC loss. To ascertain the physiopathology of the weaver condition, the development of the cerebellar cortex lobes was examined at postnatal day (P): P8, P20 and P90. Three approaches were used: 1) quantitative determination of several cerebellar features;2) qualitative evaluation of the developmental changes occurring in the cortical lobes; and 3) autoradiographic analyses of PC generation and placement.Our results revealed a reduction in the size of the wv/wv cerebellum as a whole, confirming previous results. However, as distinguished from these reports, we observed that quantified parameters contribute differently to the abnormal growth of the wv/wv cerebellar lobes.Qualitative analysis showed anomalies in wv/wv cerebellar cytoarchitecture, depending on the age and lobe analyzed. Such abnormalities included the presence of the external granular layer after P20 and, at P90, ectopic cells located in the molecular layer following several placement patterns. Finally, we obtained autoradiographic evidence that wild-type and wv/wv PCs presented similar neurogenetic timetables, as reported. However, the innovative character of this current work lies in the fact that the neurogenetic gradients of wv/wv PCs were not modified from P8 to P90. A tendency for the accumulation of late-formed PCs in the anterior and posterior lobes was found, whereas early-generated PCs were concentrated in the central and inferior lobes. These data suggested that wv/wv PCs may migrate properly to their final destinations. The extrapolation of our results to patients affected with cerebellar ataxias suggests that all cerebellar cortex lobes are affected with several age-dependent alterations in cytoarchitectonics. We also propose that PC loss may be regionally variable and not related to their neurogenetic timetables.

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From mice to men: lessons from mutant ataxic mice

Cited by 78 publications

References 322 publications

Cell death and neurodegeneration in the postnatal development of cerebellar vermis in normal and Reeler mice

Cell death and neurodegeneration in the postnatal development of cerebellar vermis in normal and Reeler mice

Recent advances in modelling of cerebellar ataxia using induced pluripotent stem cells

Cerebellar cortex development in the weaver condition presents regional and age-dependent abnormalities without differences in Purkinje cells neurogenesis

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