Mitochondrial Protection by Exogenous Otx2 in Mouse Retinal Neurons

Kim, Hyoung Tai; Kim, Soung Jung; Sohn, Young In; Paik, Sang Hyun; Caplette, Romain; Silva, Manuel; Moon, Kyeong Hwan; Lee, Eun Jung; Min, Kwang Wook; Kim, Mi Jeong; Lee, Dong-Gi; Simeone, Antonio; Lamonerie, Thomas; Furukawa, Takahisa; Choi, Jong Soon; Kweon, Hee Seok; Picaud, Serge; Kim, In Beom; Shong, Minho; Kim, Jin Woo

doi:10.1016/j.celrep.2015.09.075

Cited by 25 publications

(29 citation statements)

References 41 publications

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“…PNNs specifically capture and transfer othodenticle homeobox 2 (Otx2), an essential protein for the maturation of PV(+) interneurons 48 into the cells 49 . It has been reported that Otx2 has a neuroprotective effect by restoring mitochondrial dysfunction in mice retinas 50 . Furthermore, PNNs are found to protect PV(+) interneurons against oxidative stress in rodent prefrontal cortex 51 .…”

Section: Discussionmentioning

confidence: 99%

TGFβ signaling is associated with changes in inflammatory gene expression and perineuronal net degradation around inhibitory neurons following various neurological insults

Kim

Senatorov

Morrissey

et al. 2017

Sci Rep

104

106

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Brain damage due to stroke or traumatic brain injury (TBI), both leading causes of serious long-term disability, often leads to the development of epilepsy. Patients who develop post-injury epilepsy tend to have poor functional outcomes. Emerging evidence highlights a potential role for blood-brain barrier (BBB) dysfunction in the development of post-injury epilepsy. However, common mechanisms underlying the pathological hyperexcitability are largely unknown. Here, we show that comparative transcriptome analyses predict remodeling of extracellular matrix (ECM) as a common response to different types of injuries. ECM-related transcriptional changes were induced by the serum protein albumin via TGFβ signaling in primary astrocytes. In accordance with transcriptional responses, we found persistent degradation of protective ECM structures called perineuronal nets (PNNs) around fast-spiking inhibitory interneurons, in a rat model of TBI as well as in brains of human epileptic patients. Exposure of a naïve brain to albumin was sufficient to induce the transcriptional and translational upregulation of molecules related to ECM remodeling and the persistent breakdown of PNNs around fast-spiking inhibitory interneurons, which was contingent on TGFβ signaling activation. Our findings provide insights on how albumin extravasation that occurs upon BBB dysfunction in various brain injuries can predispose neural circuitry to the development of chronic inhibition deficits.

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Section: Discussionmentioning

confidence: 99%

TGFβ signaling is associated with changes in inflammatory gene expression and perineuronal net degradation around inhibitory neurons following various neurological insults

Kim

Senatorov

Morrissey

et al. 2017

Sci Rep

104

106

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show abstract

“…On the other hand, severe sensorineural deafness could be considered a typical manifestation of complex phenotypic spectrum caused by major mitochondrial dysfunction. Despite some experimental evidences emphasize the potential role of exogenous OTX2 in mitochondrial respiratory chain function and regulation (Kim et al, ), severe cerebellar atrophy together with myopathy and multiple mitochondrial respiratory chain defects, do not appear to be immediately correlated to OTX2 mutation and/or biological function.…”

Section: Discussionmentioning

confidence: 97%

Homozygous variant in OTX2 and possible genetic modifiers identified in a patient with combined pituitary hormone deficiency, ocular involvement, myopathy, ataxia, and mitochondrial impairment

Catania

Legati

Peverelli

et al. 2019

American J of Med Genetics Pt A

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Here we report on a singleton patient affected by a complicated congenital syndrome characterized by growth delay, retinal dystrophy, sensorineural deafness, myopathy, ataxia, combined pituitary hormone deficiency, associated with mitochondrial impairment. Targeted clinical exome sequencing led to the identification of a homozygous missense variant in OTX2. Since only dominant mutations within OTX2 have been associated with cases of syndromic microphthalmia, retinal dystrophy with or without pituitary dysfunctions, this represents the first report of an OTX2 recessive mutation. Part of the phenotype, including ataxia, myopathy and multiple mitochondrial respiratory chain defects, seemed not related to OTX2. Further analysis of next generation sequencing (NGS) data revealed additional candidate variants: a homozygous variant in LETM1, and heterozygous rare variants in AFG3L2 and POLG. All three genes encode mitochondrial proteins and the last two are known to be associated with ataxia, a neurological sign present also in the father of the proband. With our study, we aim to encourage the integration of NGS data with a detailed analysis of clinical description and family history in order to unravel composite genotypes sometimes associated with complicated phenotypes. K E Y W O R D S AFG3L2, complex congenital syndrome, LETM1, OTX2, POLG 1 | INTRODUCTION In the last decade, the development of new next generation sequencing (NGS) technologies such as whole genome/exome sequencing, has rapidly offered a growing opportunity to provide large-scale and high sensitivity genomic screening allowing the identification of new pathogenic variants associated with rare inherited diseases and overcoming most of the limitations of a candidate-gene based approach to diagnostics. Even though, complex congenital phenotypes in singleton cases, thus without a clear Mendelian inheritance pattern, still represent one of the main pitfalls of these techniques. A close interaction between clinicians and geneticists is fundamental in order to allow a proper evaluation of the NGS data, especially considering the growing number of reports about cases with intricate clinical presentation and composite genetic basis.In this report, we describe a singleton patient affected by a complicated congenital syndrome characterized by growth delay, retinal dystrophy, sensorineural deafness, myopathy, ataxia, combined pituitary hormone deficiency (CPHD), associated with mitochondrial impairment. Genetic and clinical data were deeply investigated in order to find genotype-phenotype correlations. | MATERIALS AND METHODSClinical, genetic, and histo/biochemical evaluations were performed upon acquisition of informed consent from all the subjects involved in this study, as required by the Ethical Committee of the Fondazione † Alessia Catania and Andrea Legati contributed equally to this study.

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“…On the other hand, OTX2 protein is restricted to the neurons of the central and medial-ventral VTA of the ventral midbrain (Di Salvio et al, 2010a, 2010b), and could protect VTA DA neurons against MPTP-induced neurodegeneration by down-regulating the expression of Girk2 and DAT (Di Salvio et al, 2010a, 2010b) and up-regulating the expression of neuropeptides (Chung et al, 2010). Furthermore, in retinal bipolar cells, OTX2 was reported to resist glutamate excitotoxicity (Kim et al, 2015). These results indicate that OTX2 might be an effective protective factor for neurons against the toxic effect of MPTP or other toxins, and could be used as a therapeutic target in Parkinson’s disease.…”

Section: Discussionmentioning

confidence: 99%

Tau Deficiency Down-Regulated Transcription Factor Orthodenticle Homeobox 2 Expression in the Dopaminergic Neurons in Ventral Tegmental Area and Caused No Obvious Motor Deficits in Mice

et al. 2018

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Tau protein participates in microtubule stabilization, axonal transport, and protein trafficking. Loss of normal tau function will exert a negative effect. However, current knowledge on the impact of tau deficiency on the motor behavior and related neurobiological changes is controversial. In this study, we examined motor functions and analyzed several proteins implicated in the maintenance of midbrain dopaminergic (DA) neurons (mDANs) function of adult and aged tau+/+, tau+/−, tau−/− mice. We found tau deficiency could not induce significant motor disorders. However, we discovered lower expression levels of transcription factors Orthodenticle homeobox 2 (OTX2) of mDANs in older aged mice. Compared with age-matched tau+/+ mice, there were 54.1% lower (p = 0.0192) OTX2 protein (OTX2-fluorescence intensity) in VTA DA neurons of tau+/−mice and 43.6% lower (p = 0.0249) OTX2 protein in VTA DA neurons of tau−/−mice at 18 months old. Combined with the relevant reports, our results suggested that tau deficiency alone might not be enough to mimic the pathology of Parkinson’s disease. However, OTX2 down-regulation indicates that mDANs of tau-deficient mice will be more sensitive to toxic damage from MPTP.

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Mitochondrial Protection by Exogenous Otx2 in Mouse Retinal Neurons

Cited by 25 publications

References 41 publications

TGFβ signaling is associated with changes in inflammatory gene expression and perineuronal net degradation around inhibitory neurons following various neurological insults

TGFβ signaling is associated with changes in inflammatory gene expression and perineuronal net degradation around inhibitory neurons following various neurological insults

Homozygous variant in OTX2 and possible genetic modifiers identified in a patient with combined pituitary hormone deficiency, ocular involvement, myopathy, ataxia, and mitochondrial impairment

Tau Deficiency Down-Regulated Transcription Factor Orthodenticle Homeobox 2 Expression in the Dopaminergic Neurons in Ventral Tegmental Area and Caused No Obvious Motor Deficits in Mice

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