Neurodegenerative diseases (NDs), including the most prevalent Alzheimer’s disease and Parkinson disease, share common pathological features. Despite decades of gene‐centric approaches, the molecular ...mechanisms underlying these diseases remain widely elusive. In recent years, transposable elements (TEs), long considered ‘junk’ DNA, have gained growing interest as pathogenic players in NDs. Age is the major risk factor for most NDs, and several repressive mechanisms of TEs, such as heterochromatinization, fail with age. Indeed, heterochromatin relaxation leading to TE derepression has been reported in various models of neurodegeneration and NDs. There is also evidence that certain pathogenic proteins involved in NDs (e.g., tau, TDP‐43) may control the expression of TEs. The deleterious consequences of TE activation are not well known but they could include DNA damage and genomic instability, altered host gene expression, and/or neuroinflammation, which are common hallmarks of neurodegeneration and aging. TEs might thus represent an overlooked pathogenic culprit for both brain aging and neurodegeneration. Certain pathological effects of TEs might be prevented by inhibiting their activity, pointing to TEs as novel targets for neuroprotection.
Transposable elements (TEs) are emerging as new culprits in the pathogenic pathways leading to neurodegeneration in aging‐related neurodegenerative diseases.
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BFBNIB, FZAB, GIS, IJS, KILJ, NLZOH, NUK, OILJ, SAZU, SBCE, SBMB, UL, UM, UPUK
The homeoprotein family comprises ~300 transcription factors and was long seen as primarily involved in developmental programs through cell autonomous regulation. However, recent evidence reveals ...that many of these factors are also expressed in the adult where they exert physiological functions not yet fully deciphered. Furthermore, the DNA-binding domain of most homeoproteins contains two signal sequences allowing their secretion and internalization, thus intercellular transfer. This review focuses on this new-found signaling in cell migration, axon guidance, and cerebral cortex physiological homeostasis and speculates on how it may play important roles in early arealization of the neuroepithelium. It also describes the use of homeoproteins as therapeutic proteins in mouse models of diseases affecting the central nervous system, in particular Parkinson disease and glaucoma.
Mice heterozygous for the homeobox gene Engrailed-1 (En1) display progressive loss of mesencephalic dopaminergic (mDA) neurons. We report that exogenous Engrailed-1 and Engrailed-2 (collectively ...Engrailed) protect mDA neurons from 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP), a mitochondrial complex I toxin used to model Parkinson's disease in animals. Engrailed enhances the translation of nuclearly encoded mRNAs for two key complex I subunits, Ndufs1 and Ndufs3, and increases complex I activity. Accordingly, in vivo protection against MPTP by Engrailed is antagonized by Ndufs1 small interfering RNA. An association between Engrailed and complex I is further confirmed by the reduced expression of Ndufs1 and Ndufs3 in the substantia nigra pars compacta of En1 heterozygous mice. Engrailed also confers in vivo protection against 6-hydroxydopamine and α-synuclein-A30P. Finally, the unilateral infusion of Engrailed into the midbrain increases striatal dopamine content, resulting in contralateral amphetamine-induced turning. Therefore, Engrailed is both a survival factor for adult mDA neurons and a regulator of their physiological activity.
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DOBA, IZUM, KILJ, NUK, PILJ, PNG, SAZU, UILJ, UKNU, UL, UM, UPUK
The etiology of aging-associated neurodegenerative diseases (NDs), such as Parkinson's disease (PD) and Alzheimer's disease (AD), still remains elusive and no curative treatment is available. Age is ...the major risk factor for PD and AD, but the molecular link between aging and neurodegeneration is not fully understood. Aging is defined by several hallmarks, some of which partially overlap with pathways implicated in NDs. Recent evidence suggests that aging-associated epigenetic alterations can lead to the derepression of the LINE-1 (Long Interspersed Element-1) family of transposable elements (TEs) and that this derepression might have important implications in the pathogenesis of NDs. Almost half of the human DNA is composed of repetitive sequences derived from TEs and TE mobility participated in shaping the mammalian genomes during evolution. Although most TEs are mutated and no longer mobile, more than 100 LINE-1 elements have retained their full coding potential in humans and are thus retrotransposition competent. Uncontrolled activation of TEs has now been reported in various models of neurodegeneration and in diseased human brain tissues. We will discuss in this review the potential contribution of LINE-1 elements in inducing DNA damage and genomic instability, which are emerging pathological features in NDs. TEs might represent an important molecular link between aging and neurodegeneration, and a potential target for urgently needed novel therapeutic disease-modifying interventions.
Engrailed homeoproteins are expressed in adult dopaminergic neurons of the substantia nigra. In Engrailed1 heterozygous mice, these neurons start dying at 6 weeks, are more sensitive to oxidative ...stress, and progressively develop traits similar to those observed following an acute and strong oxidative stress inflected to wild-type neurons. These changes include DNA strand breaks and the modification (intensity and distribution) of several nuclear and nucleolar heterochromatin marks. Engrailed1 and Engrailed2 are biochemically equivalent transducing proteins previously used to antagonize dopaminergic neuron death in Engrailed1 heterozygous mice and in mouse models of Parkinson disease. Accordingly, we show that, following an acute oxidative stress, a single Engrailed2 injection restores all nuclear and nucleolar heterochromatin marks, decreases the number of DNA strand breaks, and protects dopaminergic neurons against apoptosis.
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•Engrailed regulates DNA damage response and chromatin remodeling•Dopaminergic neurons are protected by Engrailed from oxidative stress•Engrailed acts both at genetic and epigenetic levels to confer neuroprotection•Engrailed homeoprotein transduction has therapeutic potential
Engrailed homeoprotein is required for the survival of adult dopaminergic neurons and can save them in Parkinson disease mouse models. Rekaik et al. show that the onset of neuronal death in En1 heterozygous knockout mice correlates with altered expression of genes involved in the DNA damage response and chromatin remodeling. Engrailed protein transduction confers neuroprotection against oxidative stress-induced double-strand breaks, nucleolar disruption, heterochromatin modifications, illegitimate gene expression, and apoptosis, protecting against oxidative stress at genetic and epigenetic levels.
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GEOZS, IJS, IMTLJ, KILJ, KISLJ, NLZOH, NUK, OILJ, PNG, SAZU, SBCE, SBJE, UILJ, UL, UM, UPUK, ZAGLJ, ZRSKP
Abstract Current research on Parkinson's disease (PD) pathogenesis requires relevant animal models that mimic the gradual and progressive development of neuronal dysfunction and degeneration that ...characterizes the disease. Polymorphisms in engrailed 1 (En1), a homeobox transcription factor that is crucial for both the development and survival of mesencephalic dopaminergic neurons, are associated with sporadic PD. This suggests that En1 mutant mice might be a promising candidate PD model. Indeed, a mouse that lacks one En1 allele exhibits decreased mitochondrial complex I activity and progressive midbrain dopamine neuron degeneration in adulthood, both features associated with PD. We aimed to further characterize the disease-like phenotype of these En1+/− mice with a focus on early neurodegenerative changes that can be utilized to score efficacy of future disease modifying studies. We observed early terminal defects in the dopaminergic nigrostriatal pathway in En1+/− mice. Several weeks before a significant loss of dopaminergic neurons in the substantia nigra could be detected, we found that striatal terminals expressing high levels of dopaminergic neuron markers TH, VMAT2, and DAT were dystrophic and swollen. Using transmission electron microscopy, we identified electron dense bodies consistent with abnormal autophagic vacuoles in these terminal swellings. In line with these findings, we detected an up-regulation of the mTOR pathway, concurrent with a downregulation of the autophagic marker LC3B, in ventral midbrain and nigral dopaminergic neurons of the En1+/− mice. This supports the notion that autophagic protein degradation is reduced in the absence of one En1 allele. We imaged the nigrostriatal pathway using the CLARITY technique and observed many fragmented axons in the medial forebrain bundle of the En1+/− mice, consistent with axonal maintenance failure. Using in vivo electrochemistry, we found that nigrostriatal terminals in the dorsal striatum were severely deficient in dopamine release and reuptake. Our findings support a progressive retrograde degeneration of En1+/− nigrostriatal neurons, akin to what is suggested to occur in PD. We suggest that using the En1+/− mice as a model will provide further key insights into PD pathogenesis, and propose that axon terminal integrity and function can be utilized to estimate dopaminergic neuron health and efficacy of experimental PD therapies.
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GEOZS, IJS, IMTLJ, KILJ, KISLJ, NUK, OILJ, PNG, SAZU, SBCE, SBJE, UL, UM, UPUK
LINE‐1 mobile genetic elements have shaped the mammalian genome during evolution. A minority of them have escaped fossilization which, when activated, can threaten genome integrity. We report that ...LINE‐1 are expressed in substantia nigra ventral midbrain dopaminergic neurons, a class of neurons that degenerate in Parkinson's disease. In Engrailed‐1 heterozygotes, these neurons show a progressive degeneration that starts at 6 weeks of age, coinciding with an increase in LINE‐1 expression. Similarly, DNA damage and cell death, induced by an acute oxidative stress applied to embryonic midbrain neurons in culture or to adult midbrain dopaminergic neurons in vivo, are accompanied by enhanced LINE‐1 expression. Reduction of LINE‐1 activity through (i) direct transcriptional repression by Engrailed, (ii) a siRNA directed against LINE‐1, (iii) the nucleoside analogue reverse transcriptase inhibitor stavudine, and (iv) viral Piwil1 expression, protects against oxidative stress in vitro and in vivo. We thus propose that LINE‐1 overexpression triggers oxidative stress‐induced DNA strand breaks and that an Engrailed adult function is to protect mesencephalic dopaminergic neurons through the repression of LINE‐1 expression.
Synopsis
Oxidative stress induces excessive DNA damage through the induction of LINE‐1 retrotransposon expression. Conversely, anti‐LINE‐1 strategies, including homeoprotein Engrailed direct repressor activity, prevent dopaminergic neuron loss. Inhibiting LINE‐1 expression or activity may thus be considered for the development of novel therapeutic strategies in neurology.
Full length LINE‐1 retrotransposons are expressed in adult mouse midbrain dopaminergic neurons.
Oxidative stress‐induced DNA strand breaks formation follows an increase in LINE‐1 expression.
LINE‐1 endonuclease ORF2p participates in the formation of DNA strand breaks.
The homeoprotein transcription factor Engrailed is a direct repressor of LINE‐1 expression.
Anti‐LINE‐1 strategies prevent dopaminergic neurodegeneration in acute oxidative stress and chronic Parkinson's disease models in mice.
The transcription factor Engrailed protects mesencephalic dopaminergic neurons by repressing the expression of the retrotransposon element LINE‐1.
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FZAB, GIS, IJS, KILJ, NLZOH, NUK, OILJ, SAZU, SBCE, SBMB, UL, UM, UPUK
Engrailed 1 and engrailed 2 homeoprotein transcription factors (collectively Engrailed) display graded expression in the chick optic tectum where they participate in retino-tectal patterning. In ...vitro, extracellular Engrailed guides retinal ganglion cell (RGC) axons and synergises with ephrin A5 to provoke the collapse of temporal growth cones. In vivo disruption of endogenous extracellular Engrailed leads to misrouting of RGC axons. Here we characterise the signalling pathway of extracellular Engrailed. Our results show that Engrailed/ephrin A5 synergy in growth cone collapse involves adenosine A1 receptor activation after Engrailed-dependent ATP synthesis, followed by ATP secretion and hydrolysis to adenosine. This is, to our knowledge, the first evidence for a role of the adenosine A1 receptor in axon guidance. Based on these results, together with higher expression of the adenosine A1 receptor in temporal than nasal growth cones, we propose a computational model that illustrates how the interaction between Engrailed, ephrin A5 and adenosine could increase the precision of the retinal projection map.
The homeoprotein Engrailed (Engrailed-1/Engrailed-2, collectively En1/2) is not only a survival factor for mesencephalic dopaminergic (mDA) neurons during development, but continues to exert ...neuroprotective and physiological functions in adult mDA neurons. Loss of one En1 allele in the mouse leads to progressive demise of mDA neurons in the ventral midbrain starting from 6weeks of age. These mice also develop Parkinson disease-like motor and non-motor symptoms. The characterization of En1 heterozygous mice have revealed striking parallels to central mechanisms of Parkinson disease pathogenesis, mainly related to mitochondrial dysfunction and retrograde degeneration. Thanks to the ability of homeoproteins to transduce cells, En1/2 proteins have also been used to protect mDA neurons in various experimental models of Parkinson disease. This neuroprotection is partly linked to the ability of En1/2 to regulate the translation of certain nuclear-encoded mitochondrial mRNAs for complex I subunits. Other transcription factors that govern mDA neuron development (e.g. Foxa1/2, Lmx1a/b, Nurr1, Otx2, Pitx3) also continue to function for the survival and maintenance of mDA neurons in the adult and act through partially overlapping but also diverse mechanisms.
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BFBNIB, FZAB, GIS, IJS, KILJ, NLZOH, NUK, OILJ, SAZU, SBCE, SBMB, UL, UM, UPUK
Age is a major risk factor for neurodegenerative diseases like Parkinson’s disease, but few studies have explored the contribution of key hallmarks of aging, namely DNA methylation changes and ...heterochromatin destructuration, in the neurodegenerative process. Here, we investigated the consequences of viral overexpression of Gadd45b, a multifactorial protein involved in DNA demethylation, in the mouse midbrain. Gadd45b overexpression induced global and stable changes in DNA methylation, particularly in introns of genes related to neuronal functions, as well as on LINE-1 transposable elements. This was paralleled by disorganized heterochromatin, increased DNA damage, and vulnerability to oxidative stress. LINE-1 de-repression, a potential source of DNA damage, preceded Gadd45b-induced neurodegeneration, whereas prolonged Gadd45b expression deregulated expression of genes related to heterochromatin maintenance, DNA methylation, or Parkinson’s disease. Our data indicates that aging-related alterations contribute to dopaminergic neuron degeneration with potential implications for Parkinson’s disease.
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•Altered DNA methylation and chromatin in dopaminergic neurons overexpressing Gadd45b•GADD45B-induced epigenetic changes affect gene expression and up-regulate LINE-1•Gadd45b overexpression leads to DNA strand breaks and dopaminergic neuron death•Dopaminergic neurons overexpressing Gadd45b are more susceptible to oxidative stress
Molecular biology; Epigenetics; Molecular neuroscience
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GEOZS, IJS, IMTLJ, KILJ, KISLJ, NLZOH, NUK, OILJ, PNG, SAZU, SBCE, SBJE, UILJ, UL, UM, UPUK, ZAGLJ, ZRSKP