Un rôle pour les astrocytes dans les déficiences intellectuelles ?

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Do Astrocytes Play a Role in Intellectual Disabilities?

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The unlikely partnership between LRRK 2 and α‐synuclein in Parkinson's disease

International audienceAbstract Our understanding of the mechanisms underlying Parkinson's disease, the once archetypical nongenetic neurogenerative disorder, has dramatically increased with the identification of α‐synuclein and LRRK 2 pathogenic mutations. While α‐synuclein protein composes the aggregates that can spread through much of the brain in disease, LRRK 2 encodes a multidomain dual‐enzyme distinct from any other protein linked to neurodegeneration. In this review, we discuss emergent datasets from multiple model systems that suggest these unlikely partners do interact in important ways in disease, both within cells that express both LRRK 2 and α‐synuclein as well as through more indirect pathways that might involve neuroinflammation. Although the link between LRRK 2 and disease can be understood in part through LRRK 2 kinase activity (phosphotransferase activity), α‐synuclein toxicity is multilayered and plausibly interacts with LRRK 2 kinase activity in several ways. We discuss common protein interactors like 14‐3‐3s that may regulate α‐synuclein and LRRK 2 in disease. Finally, we examine cellular pathways and outcomes common to both mutant α‐synuclein expression and LRRK 2 activity and points of intersection. Understanding the interplay between these two unlikely partners in disease may provide new therapeutic avenues for PD

The unlikely partnership between LRRK2 and α-synuclein in Parkinson's disease

International audienceOur understanding of the mechanisms underlying Parkinson's disease, the once archetypical nongenetic neurogenerative disorder, has dramatically increased with the identification of α-synuclein and LRRK2 pathogenic mutations. While α-synuclein protein composes the aggregates that can spread through much of the brain in disease, LRRK2 encodes a multi-domain dual-enzyme distinct from any other protein linked to neurodegeneration. In this review, we discuss emergent datasets from multiple model systems that suggests these unlikely partners do interact in important ways in disease, both within cells that express both LRRK2 and α-synuclein as well as through more indirect pathways that might involve neuroinflammation. Although the link between LRRK2 and disease can be understood in part through LRRK2 kinase activity (phospho-transferase activity), α-synuclein toxicity is multi-layered and plausibly interacts with LRRK2 kinase activity in several ways. We discuss common protein interactors like 14-3-3s that may regulate αsynuclein and LRRK2 in disease. Finally, we examine cellular pathways and outcomes common to both mutant α-synuclein expression and LRRK2 activity and points of intersection. Understanding the interplay between these two unlikely partners in disease may provide new therapeutic avenues for PD

The intellectual disability protein Oligophrenin1 controls astrocyte morphology and migration: Structural and migratory alterations in astrocytes deficient for OPHN1 via the ROCK pathway

International audienceAstrocytes are involved in several aspects of neuronal development and properties which are altered in intellectual disability (ID). Oligophrenin-1 is a RhoGAP protein implicated in actin cytoskeleton regulation, and whose mutations are associated with X-linked ID. Oligophrenin-1 is expressed in neurons, where its functions have been widely reported at the synapse, as well as in glial cells. However, its roles in astrocytes are still largely unexplored. Using in vitro and in vivo models of oligophrenin1 disruption in astrocytes, we found that oligophrenin1 regulates at the molecular level the RhoA/ROCK/MLC2 pathway in astroglial cells. We also showed at the cellular level that oligophrenin1 modulates astrocyte morphology and migration both in vitro and in vivo, and is involved in glial scar formation. Altogether, these data suggest that oligophrenin1 deficiency alters not only neuronal but also astrocytic functions, which might contribute to the development of ID

RNA toxicity in myotonic dystrophy causes pronounced spliceopathy in astrocytes, in association with defective cell adhesion and morphology, erratic migration and impaired polarization

International audienceMyotonic dystrophy type 1 (DM1) is a severe multisystemic condition. The impairment of the central nervous system (CNS) is demonstrated by cognitive and attention deficits, executive dysfunction, prevalent hypersomnia, behavioral changes, as well as intellectual disability in the most severe cases. DM1 is caused by the abnormal expansion of a non-coding trinucleotide CTG repeat. Expanded CUG transcripts accumulate in toxic RNA aggregates (or foci) in the cell nucleus, which perturb primarily the regulation of alternative splicing. Important gaps still exist in our understanding of the disease mechanisms in the brain: we do not know the cell types and the molecular pathways most predominantly affected, and how they contribute to the onset of the debilitating neurological manifestations of DM1.Using a transgenic mouse model of DM1 we found preferential accumulation of toxic RNA foci and missplicing in cortical astrocytes, relative to neurons, pointing to glia cell pathology. We used our DM1 mice as a source of primary neurons and astrocytes to resolve cell type-specific disease mechanisms by RNA sequencing of homogenous cell cultures. DM1 mouse astrocytes confirmed greater RNA foci accumulation and showed critical missplicing of transcripts that regulate cell adhesion, cytoskeleton dynamics and cell morphogenesis. Astrocyte spliceopathy translated into defective cell adhesion, reduced spreading and erratic migration in culture, as well as decreased astrocyte ramification and aberrant reorientation in DM1 mouse brains. We confirmed the abnormal splicing of relevant transcripts in brain tissue from DM1 patients, and the defective spreading of human glia cells expressing toxic CUG RNA in culture.In conclusion, we have shown the CTG repeat expansion has a deleterious impact on glia cell biology, which may impair the glial-neuronal crosstalk and synaptic function in DM1 brains, contributing to cognitive and behavioural deficits. Our results provide new insight into the cellular and molecular mechanisms of DM1 brain disease

RNA toxicity in myotonic dystrophy causes pronounced spliceopathy in astrocytes, in association with defective cell adhesion and morphology, erratic migration and impaired polarization

Myotonic dystrophy type 1 (DM1) is a severe multisystemic condition. The impairment of the central nervous system (CNS) is demonstrated by cognitive and attention deficits, executive dysfunction, prevalent hypersomnia, behavioral changes, as well as intellectual disability in the most severe cases. DM1 is caused by the abnormal expansion of a non-coding trinucleotide CTG repeat. Expanded CUG transcripts accumulate in toxic RNA aggregates (or foci) in the cell nucleus, which perturb primarily the regulation of alternative splicing. Important gaps still exist in our understanding of the disease mechanisms in the brain: we do not know the cell types and the molecular pathways most predominantly affected, and how they contribute to the onset of the debilitating neurological manifestations of DM1.Using a transgenic mouse model of DM1 we found preferential accumulation of toxic RNA foci and missplicing in cortical astrocytes, relative to neurons, pointing to glia cell pathology. We used our DM1 mice as a source of primary neurons and astrocytes to resolve cell type-specific disease mechanisms by RNA sequencing of homogenous cell cultures. DM1 mouse astrocytes confirmed greater RNA foci accumulation and showed critical missplicing of transcripts that regulate cell adhesion, cytoskeleton dynamics and cell morphogenesis. Astrocyte spliceopathy translated into defective cell adhesion, reduced spreading and erratic migration in culture, as well as decreased astrocyte ramification and aberrant reorientation in DM1 mouse brains. We confirmed the abnormal splicing of relevant transcripts in brain tissue from DM1 patients, and the defective spreading of human glia cells expressing toxic CUG RNA in culture.In conclusion, we have shown the CTG repeat expansion has a deleterious impact on glia cell biology, which may impair the glial-neuronal crosstalk and synaptic function in DM1 brains, contributing to cognitive and behavioural deficits. Our results provide new insight into the cellular and molecular mechanisms of DM1 brain disease

Myotonic dystrophy RNA toxicity alters morphology, adhesion and migration of mouse and human astrocytes

Abstract Brain dysfunction in myotonic dystrophy type 1 (DM1), the prototype of toxic RNA disorders, has been mainly attributed to neuronal RNA misprocessing, while little attention has been given to non-neuronal brain cells. Using a transgenic mouse model of DM1 that expresses mutant RNA in various brain cell types, we demonstrate that astrocytes exhibit impaired ramification and polarization in vivo and defects in adhesion, spreading and migration. RNA-dependent toxicity and phenotypes was also found in human transfected glial cells. In line with the cell phenotypes, molecular analyses revealed extensive expression and accumulation of toxic RNA in astrocytes, which resulted in RNA spliceopathy that was remarkably more severe than in neurons. Astrocyte missplicing affected primarily transcripts that regulate cell adhesion, cytoskeleton and morphogenesis, and it was confirmed in human brain tissue. We demonstrate for the first time that DM1 impacts astrocyte cell biology, possibly compromising their support and regulation of synaptic function

Myotonic dystrophy RNA toxicity alters morphology, adhesion and migration of mouse and human astrocytes

International audienceBrain dysfunction in myotonic dystrophy type 1 (DM1), the prototype of toxic RNA disorders, has been mainly attributed to neuronal RNA misprocessing, while little attention has been given to non-neuronal brain cells. Here, using a transgenic mouse model of DM1 that expresses mutant RNA in various brain cell types (neurons, astroglia, and oligodendroglia), we demonstrate that astrocytes exhibit impaired ramification and polarization in vivo and defects in adhesion, spreading, and migration. RNA-dependent toxicity and phenotypes are also found in human transfected glial cells. In line with the cell phenotypes, molecular analyses reveal extensive expression and accumulation of toxic RNA in astrocytes, which result in RNA spliceopathy that is more severe than in neurons. Astrocyte missplicing affects primarily transcripts that regulate cell adhesion, cytoskeleton, and morphogenesis, and it is confirmed in human brain tissue. Our findings demonstrate that DM1 impacts astrocyte cell biology, possibly compromising their support and regulation of synaptic function

The C-Terminal Domain of LRRK2 with the G2019S Substitution Increases Mutant A53T α-Synuclein Toxicity in Dopaminergic Neurons In Vivo

International audienceAlpha-synuclein (α-syn) and leucine-rich repeat kinase 2 (LRRK2) play crucial roles in Parkinson’s disease (PD). They may functionally interact to induce the degeneration of dopaminergic (DA) neurons via mechanisms that are not yet fully understood. We previously showed that the C-terminal portion of LRRK2 (ΔLRRK2) with the G2019S mutation (ΔLRRK2G2019S) was sufficient to induce neurodegeneration of DA neurons in vivo, suggesting that mutated LRRK2 induces neurotoxicity through mechanisms that are (i) independent of the N-terminal domains and (ii) “cell-autonomous”. Here, we explored whether ΔLRRK2G2019S could modify α-syn toxicity through these two mechanisms. We used a co-transduction approach in rats with AAV vectors encoding ΔLRRK2G2019S or its “dead” kinase form, ΔLRRK2DK, and human α-syn with the A53T mutation (AAV-α-synA53T). Behavioral and histological evaluations were performed at 6- and 15-weeks post-injection. Results showed that neither form of ΔLRRK2 alone induced the degeneration of neurons at these post-injection time points. By contrast, injection of AAV-α-synA53T alone resulted in motor signs and degeneration of DA neurons. Co-injection of AAV-α-synA53T with AAV-ΔLRRK2G2019S induced DA neuron degeneration that was significantly higher than that induced by AAV-α-synA53T alone or with AAV-ΔLRRK2DK. Thus, mutated α-syn neurotoxicity can be enhanced by the C-terminal domain of LRRK2G2019 alone, through cell-autonomous mechanisms