Neurobehavioral deficits in the KIKO mouse model of Friedreich’s ataxia

McMackin, Marissa Z.; Henderson, Chelsea K.; Cortopassi, Gino A

doi:10.1016/j.bbr.2016.08.053

Cited by 25 publications

(25 citation statements)

References 35 publications

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“…We first examined the levels of frataxin and the mitochondrial biogenesis master regulator PGC-1α in cerebellar homogenates of KIKO mice at both asymptomatic [postnatal day (P) 30, P90, P180] and symptomatic (P270) ages ( McMackin et al, 2016 ). In wild-type control mice, frataxin and PGC-1α levels are slightly decreased or remain unaltered in cerebellar homogenates at P180 and P270 compared with P30 and P90 ( …”

Section: Resultsmentioning

confidence: 99%

“…No overt neuronal loss appears in initial studies, but mRNA panels from tissue share many features with those from patients ( Miranda et al, 2002 ). More sophisticated studies in KIKO mice identify significant neurobehavioral deficits in inverted screen, treadscan and Von Frey tasks at >8 months of age, resembling clinical manifestations of cerebellar gait ataxia, decreased peripheral sensitivity, and decreased motor strength and endurance in late-onset FRDA patients ( McMackin et al, 2016 ). Thus, the KIKO mouse constitutes a suitable model to search for early pathophysiological changes of FRDA by examining its physiological and biochemical properties at asymptomatic ages (1, 3 and 6 months of age).…”

Section: Introductionmentioning

confidence: 99%

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Early cerebellar deficits in mitochondrial biogenesis and respiratory chain complexes in the KIKO mouse model of Friedreich ataxia

Lin

Magrané

Rattelle

et al. 2017

Disease Models &Amp; Mechanisms

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Friedreich ataxia (FRDA), the most common recessive inherited ataxia, results from deficiency of frataxin, a small mitochondrial protein crucial for iron-sulphur cluster formation and ATP production. Frataxin deficiency is associated with mitochondrial dysfunction in FRDA patients and animal models; however, early mitochondrial pathology in FRDA cerebellum remains elusive. Using frataxin knock-in/knockout (KIKO) mice and KIKO mice carrying the mitoDendra transgene, we show early cerebellar deficits in mitochondrial biogenesis and respiratory chain complexes in this FRDA model. At asymptomatic stages, the levels of PGC-1α (PPARGC1A), the mitochondrial biogenesis master regulator, are significantly decreased in cerebellar homogenates of KIKO mice compared with age-matched controls. Similarly, the levels of the PGC-1α downstream effectors, NRF1 and Tfam, are significantly decreased, suggesting early impaired cerebellar mitochondrial biogenesis pathways. Early mitochondrial deficiency is further supported by significant reduction of the mitochondrial markers GRP75 (HSPA9) and mitofusin-1 in the cerebellar cortex. Moreover, the numbers of Dendra-labeled mitochondria are significantly decreased in cerebellar cortex, confirming asymptomatic cerebellar mitochondrial biogenesis deficits. Functionally, complex I and II enzyme activities are significantly reduced in isolated mitochondria and tissue homogenates from asymptomatic KIKO cerebella. Structurally, levels of the complex I core subunit NUDFB8 and complex II subunits SDHA and SDHB are significantly lower than those in age-matched controls. These results demonstrate complex I and II deficiency in KIKO cerebellum, consistent with defects identified in FRDA patient tissues. Thus, our findings identify early cerebellar mitochondrial biogenesis deficits as a potential mediator of cerebellar dysfunction and ataxia, thereby providing a potential therapeutic target for early intervention of FRDA.

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Section: Resultsmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

Early cerebellar deficits in mitochondrial biogenesis and respiratory chain complexes in the KIKO mouse model of Friedreich ataxia

Lin

Magrané

Rattelle

et al. 2017

Disease Models &Amp; Mechanisms

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“…Herein, we used KIKO mouse that represents a suitable in vivo model for studying neurodegeneration as well as metabolic complications in FRDA 17,22 . We firstly monitored body weight and a trend to gain weight was observed in 6 months KIKO mice that becomes significant at 8 months of age (Fig.…”

Section: Alteration Of Basal Metabolic Parameters In Kiko Micementioning

confidence: 99%

Frataxin deficiency induces lipid accumulation and affects thermogenesis in brown adipose tissue

et al. 2020

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Decreased expression of mitochondrial frataxin (FXN) causes Friedreich's ataxia (FRDA), a neurodegenerative disease with type 2 diabetes (T2D) as severe comorbidity. Brown adipose tissue (BAT) is a mitochondria-enriched and antidiabetic tissue that turns excess energy into heat to maintain metabolic homeostasis. Here we report that the FXN knock-in/knock-out (KIKO) mouse shows hyperlipidemia, reduced energy expenditure and insulin sensitivity, and elevated plasma leptin, recapitulating T2D-like signatures. FXN deficiency leads to disrupted mitochondrial ultrastructure and oxygen consumption as well as lipid accumulation in BAT. Transcriptomic data highlights cold intolerance in association with iron-mediated cell death (ferroptosis). Impaired PKA-mediated lipolysis and expression of genes controlling mitochondrial metabolism, lipid catabolism and adipogenesis were observed in BAT of KIKO mice as well as in FXN-deficient T37i brown and primary adipocytes. Significant susceptibility to ferroptosis was observed in adipocyte precursors that showed increased lipid peroxidation and decreased glutathione peroxidase 4. Collectively our data point to BAT dysfunction in FRDA and suggest BAT as promising therapeutic target to overcome T2D in FRDA.

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“…No overt neuronal loss appears in initial studies but mRNA panels from tissue share many features with those from patients ( Miranda et al, 2002 ). Recent neurobehavioral studies in KIKO mice show cerebellar ataxia, decreased peripheral sensitivity, and decreased motor strength and endurance at 9 months of age, resembling clinical manifestations observed in late-onset FRDA patients ( McMackin et al, 2016 ). This phenotypically abnormal mouse with solid biochemical deficits, but no overt cell loss, thus provides a model to search for CNS abnormalities that mediate the earliest cerebellar features of FRDA.…”

Section: Introductionmentioning

confidence: 69%

Early VGLUT1-specific parallel fiber synaptic deficits and dysregulated cerebellar circuit in the KIKO mouse model of Friedreich ataxia

Lin

Magrané

Clark

et al. 2017

Disease Models &Amp; Mechanisms

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Friedreich ataxia (FRDA) is an autosomal recessive neurodegenerative disorder with progressive ataxia that affects both the peripheral and central nervous system (CNS). While later CNS neuropathology involves loss of large principal neurons and glutamatergic and GABAergic synaptic terminals in the cerebellar dentate nucleus, early pathological changes in FRDA cerebellum remain largely uncharacterized. Here, we report early cerebellar VGLUT1 (SLC17A7)-specific parallel fiber (PF) synaptic deficits and dysregulated cerebellar circuit in the frataxin knock-in/knockout (KIKO) FRDA mouse model. At asymptomatic ages, VGLUT1 levels in cerebellar homogenates are significantly decreased, whereas VGLUT2 (SLC17A6) levels are significantly increased, in KIKO mice compared with age-matched controls. Additionally, GAD65 (GAD2) levels are significantly increased, while GAD67 (GAD1) levels remain unaltered. This suggests early VGLUT1-specific synaptic input deficits, and dysregulation of VGLUT2 and GAD65 synaptic inputs, in the cerebellum of asymptomatic KIKO mice. Immunohistochemistry and electron microscopy further show specific reductions of VGLUT1-containing PF presynaptic terminals in the cerebellar molecular layer, demonstrating PF synaptic input deficiency in asymptomatic and symptomatic KIKO mice. Moreover, the parvalbumin levels in cerebellar homogenates and Purkinje neurons are significantly reduced, but preserved in other interneurons of the cerebellar molecular layer, suggesting specific parvalbumin dysregulation in Purkinje neurons of these mice. Furthermore, a moderate loss of large principal neurons is observed in the dentate nucleus of asymptomatic KIKO mice, mimicking that of FRDA patients. Our findings thus identify early VGLUT1-specific PF synaptic input deficits and dysregulated cerebellar circuit as potential mediators of cerebellar dysfunction in KIKO mice, reflecting developmental features of FRDA in this mouse model.

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Neurobehavioral deficits in the KIKO mouse model of Friedreich’s ataxia

Cited by 25 publications

References 35 publications

Early cerebellar deficits in mitochondrial biogenesis and respiratory chain complexes in the KIKO mouse model of Friedreich ataxia

Early cerebellar deficits in mitochondrial biogenesis and respiratory chain complexes in the KIKO mouse model of Friedreich ataxia

Frataxin deficiency induces lipid accumulation and affects thermogenesis in brown adipose tissue

Early VGLUT1-specific parallel fiber synaptic deficits and dysregulated cerebellar circuit in the KIKO mouse model of Friedreich ataxia

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