A role for astrocytes in cerebellar deficits in frataxin deficiency: Protection by insulin-like growth factor I

Franco, C. M.; Genı́s, Laura; Navarro, JA; Pérez-Domper, Paloma; Fernández, Adolfo; Schneuwly, Stephan; Alemán, Ignacio Torres

doi:10.1016/j.mcn.2017.02.008

Cited by 23 publications

(29 citation statements)

References 55 publications

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“…A similar involvement of oxidative stress in neurodegeneration was also proposed for Friedreich ataxia, in light of the abnormal levels of antioxidant enzymes found in the cerebella of frataxin-depleted mice [60]. In a Drosophila model of this disease, the expression of the mutant frataxin protein in glial cells was indeed shown to increase lipid peroxidation, inducing mitochondrial dysfunction and, in turn, accumulation of fatty acids and cell degeneration, which translated in a shortened lifespan and impaired locomotor performances [59].…”

Section: When Astrocytes "Burn Out": Stressed Astrocytes Cause Accumumentioning

confidence: 55%

“…To mimic frataxin deficiency, animal models were developed in which the wild-type FXN gene was ubiquitously silenced, resulting in neuronal degeneration, motor impairments, and reduced lifespan. Interestingly, specific deletion of this gene in glial cells in Drosophila generated FA-like symptoms comparable to those of the whole-body knockout flies [59], and its ablation in developing mice from GFAP-expressing neuronal and astrocyte precursors resulted in severe ataxia and early death, associated with growth and survival impairments in cerebellar astrocytes [60]. Although, in this mouse model, the contribution of mutant neuronal and astrocyte precursors could not be discriminated, the evidence that the alterations observed were specific for cerebellar astrocytes and absent in forebrain astrocytes suggests that a greater vulnerability of developing cerebellar astrocytes to frataxin depletion may contribute to the highly specific cerebellar disturbances typical of FA.…”

Section: Astrocytes Involvement In Ataxia As Revealed By Astrocyte-spmentioning

confidence: 99%

“…For instance, the available animal models for AT do not show robust neurodegeneration or cerebellar atrophy, hallmarks of the human disease [130], while a mouse model of SCA1 in which the mutant ATXN1 was expressed at the endogenous level only showed mild behavioral impairments [46]. Similarly, an insufficient reduction of frataxin in FA mouse models translated into the absence of anomalies in motor coordination [60,131,132]. These effects, partially due to the short lifespan of mice that does not allow the neurons to accumulate significant damage, were often overcome by creating new animal models with transgenes expression exceeding the endogenous levels, which in turn led to dramatic and exaggerated outcomes that again did not reflect reality [56,133].…”

Section: Conclusion and Future Perspectivesmentioning

confidence: 99%

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Cerebellar Astrocytes: Much More Than Passive Bystanders In Ataxia Pathophysiology

Cerrato

2020

JCM

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Ataxia is a neurodegenerative syndrome, which can emerge as a major element of a disease or represent a symptom of more complex multisystemic disorders. It comprises several forms with a highly variegated etiology, mainly united by motor, balance, and speech impairments and, at the tissue level, by cerebellar atrophy and Purkinje cells degeneration. For this reason, the contribution of astrocytes to this disease has been largely overlooked in the past. Nevertheless, in the last few decades, growing evidences are pointing to cerebellar astrocytes as crucial players not only in the progression but also in the onset of distinct forms of ataxia. Although the current knowledge on this topic is very fragmentary and ataxia type-specific, the present review will attempt to provide a comprehensive view of astrocytes’ involvement across the distinct forms of this pathology. Here, it will be highlighted how, through consecutive stage-specific mechanisms, astrocytes can lead to non-cell autonomous neurodegeneration and, consequently, to the behavioral impairments typical of this disease. In light of that, treating astrocytes to heal neurons will be discussed as a potential complementary therapeutic approach for ataxic patients, a crucial point provided the absence of conclusive treatments for this disease.

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Section: When Astrocytes "Burn Out": Stressed Astrocytes Cause Accumumentioning

confidence: 55%

Section: Astrocytes Involvement In Ataxia As Revealed By Astrocyte-spmentioning

confidence: 99%

Section: Conclusion and Future Perspectivesmentioning

confidence: 99%

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Cerebellar Astrocytes: Much More Than Passive Bystanders In Ataxia Pathophysiology

Cerrato

2020

JCM

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“…In addition, insulin-like growth factor I (IGF-I) has shown therapeutic effects in different cerebellar ataxias due to its protective effects on mitochondrial function and neuroprotective effects in frataxin deficient neuronal cultures 38 and Fxn-deficient mice 39 . Furthermore, diabetes is a metabolic disorder that affects one in every three Friedreich’s ataxia patients.…”

Section: Discussionmentioning

confidence: 99%

Circulating miR-323-3p is a biomarker for cardiomyopathy and an indicator of phenotypic variability in Friedreich’s ataxia patients

Seco-Cervera

González-Rodríguez

Ibáñez-Cabellos

et al. 2017

Sci Rep

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MicroRNAs (miRNAs) are noncoding RNAs that contribute to gene expression modulation by regulating important cellular pathways. In this study, we used small RNA sequencing to identify a series of circulating miRNAs in blood samples taken from Friedreich's ataxia patients. We were thus able to develop a miRNA biomarker signature to differentiate Friedreich's ataxia (FRDA) patients from healthy people. Most research on FDRA has focused on understanding the role of frataxin in the mitochondria, and a whole molecular view of pathological pathways underlying FRDA therefore remains to be elucidated. We found seven differentially expressed miRNAs, and we propose that these miRNAs represent key mechanisms in the modulation of several signalling pathways that regulate the physiopathology of FRDA. If this is the case, miRNAs can be used to characterize phenotypic variation in FRDA and stratify patients' risk of cardiomyopathy. In this study, we identify miR-323-3p as a candidate marker for phenotypic differentiation in FRDA patients suffering from cardiomyopathy. We propose the use of dynamic miRNAs as biomarkers for phenotypic characterization and prognosis of FRDA.Friedreich's ataxia (FRDA), an autosomal recessive neurodegenerative mitochondrial disease, is the most prevalent hereditary ataxia in people of European descent, affecting around 2-5 people in every 100,000 (Orphanet reports). This rare, childhood-onset disease is characterized by a progressive loss of sensory neurons in the dorsal root ganglia (DRG) and posterior columns. This loss of neurons is followed by degeneration of corticospinal and spinocerebellar tracts of the spinal cord, culminating in gait and limb ataxia, loss of tendon reflexes and dysarthria 1, 2 . The cerebellar dentate nucleus is also affected 3 . Other non-neurological features of FRDA are scoliosis, diabetes and cardiac symptoms [4][5][6] . Hypertrophic cardiomyopathy, which is found in two thirds of FRDA patients at the time of diagnosis, is the primary cause of death in these patients 7,8 . FRDA is most often caused by a homozygous GAA repeat expansion mutation (typically between 600 and 1200 repeats) in the first intron of the frataxin gene (FXN), which is found on chromosome 9q21.11 and encodes the protein frataxin 2, 9 . The elevated number of GAA repeats and resulting blockage effects on the RNAPII transcription machinery ("sticky DNA", hairpin structures, parallel duplex structures, R-loops, etc.; reviewed in ref. 10) have been proposed as causes of decreased expression of the mitochondrial protein frataxin 11 . The frataxin

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“…Since orexin neurons express IGF-I receptors (Figure 1), we inactivated them to determine their role in orexinergic function. We genetically ablated IGF-IR activity using the Cre/Lox system following previous published procedures 36 . Mice with inactive IGF-IR in orexin neurons (Firoc mice) express a truncated IGF-IR in the hypothalamus, as determined by PCR detection of the truncated IGF-IR ( Figure 1A).…”

Section: Inactivation Of Igf-ir In Orexin Neuronsmentioning

confidence: 99%

Insulin-Like Growth Factor I Modulates Sleep Through Hypothalamic Orexin Neurons

Zegarra-Valdivia

Pignatelli

Sevilla

et al. 2020

Preprint

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Although metabolic and sleep disturbances are commonly associated, the underlying processes are not yet fully defined. Insulin-like growth factor-I (IGF-I), an anabolic hormone that shows a circadian pattern in the circulation, is associated to sleep regulation along evolution. However, its role in this universal homeostatic process remains poorly understood. We now report that the activity of orexin neurons, a discrete cell population in the lateral hypothalamus that is involved in the circadian sleep/wake cycle, is modulated by circulating IGF-I. Furthermore, mice with blunted IGF-I receptor activity in orexin neurons have lower levels of orexin in the hypothalamus, show altered electrocorticographic patterns with predominant slow wave activity, reduced onset-sleep latency, and less transitions between sleep and awake stages. Collectively, these results extend the role of this pleiotropic growth factor to shaping sleep architecture through regulation of orexin neurons. We speculate that poor sleep quality associated to diverse conditions may be related to disturbed brain IGF-I input to orexin neurons.

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A role for astrocytes in cerebellar deficits in frataxin deficiency: Protection by insulin-like growth factor I

Cited by 23 publications

References 55 publications

Cerebellar Astrocytes: Much More Than Passive Bystanders In Ataxia Pathophysiology

Cerebellar Astrocytes: Much More Than Passive Bystanders In Ataxia Pathophysiology

Circulating miR-323-3p is a biomarker for cardiomyopathy and an indicator of phenotypic variability in Friedreich’s ataxia patients

Insulin-Like Growth Factor I Modulates Sleep Through Hypothalamic Orexin Neurons

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