Preventive motor training but not progenitor grafting ameliorates cerebellar ataxia and deregulated autophagy in tambaleante mice

Fucà, Elisa; Guglielmotto, Michela; Boda, Enrica; Rossi, Ferdinando; Leto, Ketty; Buffo, Annalisa

doi:10.1016/j.nbd.2017.02.005

Cited by 26 publications

(11 citation statements)

References 77 publications

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“…We initially observed clear motor abnormalities in a number of adult mutant mice, suggesting possible cerebellar defects. To precisely address functional cerebellar abnormalities in Sox2 mutants, we subjected them to behavioral tests of motor coordination and equilibrium, used to detect alterations that arise following cerebellar damage: the rotarod and balance beam tests (Fuca et al, ; Hilber & Caston, ). We compared motor performances of mutants and control littermates between 1 and 8 months of life (Figure b–d).…”

Section: Resultsmentioning

confidence: 99%

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Sox2 conditional mutation in mouse causes ataxic symptoms, cerebellar vermis hypoplasia, and postnatal defects of Bergmann glia

Cerrato

Mercurio

Leto

et al. 2018

Glia

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Sox2 is a transcription factor active in the nervous system, within different cell types, ranging from radial glia neural stem cells to a few specific types of differentiated glia and neurons. Mutations in the human SOX2 transcription factor gene cause various central nervous system (CNS) abnormalities, involving hippocampus and eye defects, as well as ataxia. Conditional Sox2 mutation in mouse, with different Cre transgenes, previously recapitulated different essential features of the disease, such as hippocampus and eye defects. In the cerebellum, Sox2 is active from early embryogenesis in the neural progenitors of the cerebellar primordium; Sox2 expression is maintained, postnatally, within Bergmann glia (BG), a differentiated cell type essential for Purkinje neurons functionality and correct motor control. By performing Sox2 Cre-mediated ablation in the developing and postnatal mouse cerebellum, we reproduced ataxia features. Embryonic Sox2 deletion (with Wnt1Cre) leads to reduction of the cerebellar vermis, known to be commonly related to ataxia, preceded by deregulation of Otx2 and Gbx2, critical regulators of vermis development. Postnatally, BG is progressively disorganized, mislocalized, and reduced in mutants. Sox2 postnatal deletion, specifically induced in glia (with GLAST-CreERT2), reproduces the BG defect, and causes (milder) ataxic features. Our results define a role for Sox2 in cerebellar function and development, and identify a functional requirement for Sox2 within postnatal BG, of potential relevance for ataxia in mouse mutants, and in human patients.

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Section: Resultsmentioning

confidence: 99%

“…Motor coordination, balance, and motor learning were assessed using an accelerating rotarod (Ugo Basile, Varese, Italy; Fuca et al, ). The rotarod apparatus had five flanges dividing the five 5.7‐cm lanes, the cylinder diameter was 3.5 cm.…”

Section: Methodsmentioning

confidence: 99%

Sox2 conditional mutation in mouse causes ataxic symptoms, cerebellar vermis hypoplasia, and postnatal defects of Bergmann glia

Cerrato

Mercurio

Leto

et al. 2018

Glia

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“…Consistently, pharmacological treatments targeting autophagy provided beneficial effects in several models of hereditary cerebellar ataxia [168][169][170][171]. Moreover, positive outcomes associated with changes in autophagy were also induced by motor training administered at presymptomatic stages in the tambaleante (tbl) mouse model of ataxia [172]. In tbl mice [173], alteration of the HERC1 E3 ubiquitin ligase leads to overactive autophagic processes resulting in massive degeneration of Purkinje neurons [163].…”

Section: Cellular Mechanisms Underlying Functional Cerebellar Reservementioning

confidence: 89%

“…In tbl mice [173], alteration of the HERC1 E3 ubiquitin ligase leads to overactive autophagic processes resulting in massive degeneration of Purkinje neurons [163]. Motor exercise favored tbl Purkinje neuron survival, reduced atrophy, increased afferent contacts to mutant Purkinje neurons, and allowed partial circuit stabilization, with moderate positive motor consequences [172]. This was accompanied by autophagy attenuation and increased BDNF, a key signal underlying both neuroprotection and neural plasticity [174].…”

Section: Cellular Mechanisms Underlying Functional Cerebellar Reservementioning

confidence: 99%

Consensus Paper. Cerebellar Reserve: From Cerebellar Physiology to Cerebellar Disorders

et al. 2019

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Cerebellar reserve refers to the capacity of the cerebellum to compensate for tissue damage or loss of function resulting from many different etiologies. When the inciting event produces acute focal damage (e.g., stroke, trauma), impaired cerebellar function may be compensated for by other cerebellar areas or by extracerebellar structures (i.e., structural cerebellar reserve). In contrast, when pathological changes compromise cerebellar neuronal integrity gradually leading to cell death (e.g., metabolic and immune-mediated cerebellar ataxias, neurodegenerative ataxias), it is possible that the affected area itself can compensate for the slowly evolving cerebellar lesion (i.e., functional cerebellar reserve). Here, we examine cerebellar reserve from the perspective of the three cornerstones of clinical ataxiology: control of ocular movements, coordination of voluntary axial and appendicular movements, and cognitive functions. Current evidence indicates that cerebellar reserve is potentiated by environmental enrichment through the mechanisms of autophagy and synaptogenesis, suggesting that cerebellar reserve is not rigid or fixed, but exhibits plasticity potentiated by experience. These conclusions have therapeutic implications. During the period when cerebellar reserve is preserved, treatments should be directed at stopping disease progression and/or limiting the pathological process. Simultaneously, cerebellar reserve may be potentiated using multiple approaches. Potentiation of cerebellar reserve may lead to compensation and restoration of function in the setting of cerebellar diseases, and also in disorders primarily of the cerebral hemispheres by enhancing cerebellar mechanisms of action. It therefore appears that cerebellar reserve, and the underlying plasticity of cerebellar microcircuitry that enables it, may be of critical neurobiological importance to a wide range of neurological/neuropsychiatric conditions.

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“…Studies in rats and mice showed that motor training prevents or reduces cerebellar degeneration caused by alcoholicinduced degeneration disease, age, and also SCA 1 (mouse model) (Carro et al 2001;Larsen et al 2000;Fryer et al 2011). Fuca et al (2017) found that motor training led to increased survival of Purkinje cells and cerebellar circuitry in tambaleante mutant mice. Exercising demanding and new complex multi-joint movements appear to outperform "pure exercise" (Klintsova et al 2004;Kleim et al 2007;Black et al 1990).…”

Section: Animal Cerebellar Lesion Models Indicate Long-term Adaptatiomentioning

confidence: 99%

General Management of Cerebellar Disorders: An Overview

Ilg¹,

Timmann²

2020

Handbook of the Cerebellum and Cerebellar Disorders

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Cerebellar disorders primarily affect motor functions and can lead to significant and serious restrictions in activities of daily living. Possibilities for medical interventions are rare and limited to specific diseases and symptoms. Furthermore, motor rehabilitation for patients suffering from cerebellar damage is challenging, since the cerebellum is known to play an important role for the execution as well as for the (re)-learning of precise movements. This chapter reviews the current state of the art in medical intervention and rehabilitation, focusing on presenting new results on motor rehabilitation in cerebellar disease. Recent studies indicate that even in the case of degenerative cerebellar diseases, intensive and continuous motor training can reduce ataxia symptoms and increase motor performance relevant to daily living. In addition, current studies in the area of motor learningin combination with modern imaging techniquesin cerebellar disease are described. These results offer promising perspectives for a deeper understanding of remaining motor learning capacities in cerebellar disease and thus might help in the future to optimize motor rehabilitation for individual patients.

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Preventive motor training but not progenitor grafting ameliorates cerebellar ataxia and deregulated autophagy in tambaleante mice

Cited by 26 publications

References 77 publications

Sox2 conditional mutation in mouse causes ataxic symptoms, cerebellar vermis hypoplasia, and postnatal defects of Bergmann glia

Sox2 conditional mutation in mouse causes ataxic symptoms, cerebellar vermis hypoplasia, and postnatal defects of Bergmann glia

Consensus Paper. Cerebellar Reserve: From Cerebellar Physiology to Cerebellar Disorders

General Management of Cerebellar Disorders: An Overview

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