C9ORF72 knockdown triggers FTD-like symptoms and cell pathology in mice

The GGGGCC intronic repeat expansion within C9ORF72 is the most common genetic cause of ALS and FTD. This mutation results in toxic gain of function through accumulation of expanded RNA foci and aggregation of abnormally translated dipeptide repeat proteins, as well as loss of function due to impaired transcription of C9ORF72. A number of in vivo and in vitro models of gain and loss of function effects have suggested that both mechanisms synergize to cause the disease. However, the contribution of the loss of function mechanism remains poorly understood. We have generated C9ORF72 knockdown mice to mimic C9-FTD/ALS patients haploinsufficiency and investigate the role of this loss of function in the pathogenesis. We found that decreasing C9ORF72 leads to anomalies of the autophagy/lysosomal pathway, cytoplasmic accumulation of TDP-43 and decreased synaptic density in the cortex. Knockdown mice also developed FTD-like behavioral deficits and mild motor phenotypes at a later stage. These findings show that C9ORF72 partial loss of function contributes to the damaging events leading to C9-FTD/ALS

Gain of Olig2 function in oligodendrocyte progenitors promotes remyelination

The basic helix-loop-helix transcription factor Olig2 is a key determinant for the specification of neural precursor cells into oligodendrocyte progenitor cells. However, the functional role of Olig2 in oligodendrocyte migration and differentiation remains elusive both during developmental myelination and under demyelinating conditions of the adult central nervous system. To decipher Olig2 functions, we generated transgenic mice (TetOlig2:Sox10rtTA/+) overexpressing Olig2 in Sox10+ oligodendroglial cells in a doxycycline inducible manner. We show that Olig2 overexpression increases the generation of differentiated oligodendrocytes, leading to precocious myelination of the central nervous system. Unexpectedly, we found that gain of Olig2 function in oligodendrocyte progenitor cells enhances their migration rate. To determine whether Olig2 overexpression in adult oligodendrocyte progenitor cells promotes oligodendrocyte regeneration for myelin repair, we induced lysophosphatidylcholine demyelination in the corpus callosum of TetOlig2:Sox10rtTA/+ and control mice. We found that Olig2 overexpression enhanced oligodendrocyte progenitor cell differentiation and remyelination. To assess the relevance of these findings in demyelinating diseases, we also examined OLIG2 expression in multiple sclerosis lesions. We demonstrate that OLIG2 displays a differential expression pattern in multiple sclerosis lesions that correlates with lesion activity. Strikingly, OLIG2 was predominantly detected in NOGO-A+ (now known as RTN4-A) maturing oligodendrocytes, which prevailed in active lesion borders, rather than chronic silent and shadow plaques. Taken together, our data provide proof of principle indicating that OLIG2 overexpression in oligodendrocyte progenitor cells might be a possible therapeutic mechanism for enhancing myelin repair

Tocopherol Derivative TFA-12 Promotes Myelin Repair in Experimental Models of Multiple Sclerosis

Multiple sclerosis (MS) is an inflammatory disease of the CNS that is associated with demyelination and axonal loss, resulting in severe neurological handicap. Current MS therapies mostly target neuroinflammation but have only a little impact on CNS myelin repair. Progress toward treatments that enhance remyelination would therefore represent major advances in MS treatment. Here, we examined the ability of TFA-12, a new synthetic compound belonging to tocopherol long-chain fatty alcohols, to promote oligodendrocyte regeneration and remyelination in experimental models of MS. We showed that TFA-12 significantly ameliorates neurological deficit and severity of myelin oligodendrocyte glycoprotein-induced experimental autoimmune encephalomyelitis (EAE) in mice. Histological evaluation of mouse EAE spinal cords showed that TFA-12 treatment reduces inflammation, astrogliosis, and myelin loss. Additionally, we demonstrated that TFA-12 accelerates remyelination of focal demyelinated lesions induced by lysolecithin injections.Wealso found that this compound induces the differentiation of oligodendrocyte precursor cells into mature oligodendrocytes through the inhibition of the Notch/Jagged1 signaling pathway. Altogether, our data provide important proof of principle indicating that TFA-12 could be a potential therapeutic compound for myelin repair in MS.Fil: Blanchard, Benoit. Universite Pierre et Marie Curie; Francia; . Centre National de la Recherche Scientifique. Unités Mixtes de Recherche; Francia; . Institut National de la Santé et de la Recherche Médicale; FranciaFil: Heurtaux, Tony. Université du Luxembourg. Faculté des Sciences, de la Technologie et de la Communication. Laboratoire de Neurobiologie. Life Sciences Research Unit; Luxemburgo;Fil: Garcia, Corina Ileana. Universidad de Buenos Aires. Facultad de Farmacia y Bioquímica. Departamento de Farmacología. Cátedra de Química Medicinal; Argentina. Institut National de la Santé et de la Recherche Médicale; Francia. Universite Pierre et Marie Curie; Francia;Fil: Moll, Natalia M.. Institut National de la Santé et de la Recherche Médicale; . Universite Pierre et Marie Curie; Francia; . Centre National de la Recherche Scientifique. Unités Mixtes de Recherche; Francia;Fil: Caillava, Céline. Institut National de la Santé et de la Recherche Médicale; . Universite Pierre et Marie Curie; Francia; . Centre National de la Recherche Scientifique. Unités Mixtes de Recherche; Francia;Fil: Grandbarbe, Luc. Université du Luxembourg. Faculté des Sciences, de la Technologie et de la Communication. Laboratoire de Neurobiologie. Life Sciences Research Unit; Luxemburgo;Fil: Klosptein, Armelle. Institut National de la Santé et de la Recherche Médicale; . Universite Pierre et Marie Curie; Francia; . Centre National de la Recherche Scientifique. Unités Mixtes de Recherche; Francia;Fil: Kerninon, Christophe. Institut National de la Santé et de la Recherche Médicale; . Universite Pierre et Marie Curie; Francia; . Centre National de la Recherche Scientifique. Unités Mixtes de Recherche; Francia;Fil: Frah, Magali. Institut National de la Santé et de la Recherche Médicale; . Universite Pierre et Marie Curie; Francia; . Centre National de la Recherche Scientifique. Unités Mixtes de Recherche; Francia;Fil: Coowar, Djalil. AxoGlia Therapeutics; Luxemburgo;Fil: Baron-van Evercooren, Anne. Institut National de la Santé et de la Recherche Médicale; . Universite Pierre et Marie Curie; Francia; . Centre National de la Recherche Scientifique. Unités Mixtes de Recherche; Francia;Fil: Morga, Eleonora. Université du Luxembourg. Faculté des Sciences, de la Technologie et de la Communication. Laboratoire de Neurobiologie. Life Sciences Research Unit; Luxemburgo;Fil: Heuschling, Paul. Université du Luxembourg. Faculté des Sciences, de la Technologie et de la Communication. Laboratoire de Neurobiologie. Life Sciences Research Unit; Luxemburgo;Fil: Nait Oumesmar, Brahim. Institut National de la Santé et de la Recherche Médicale; . Universite Pierre et Marie Curie; Francia; . Centre National de la Recherche Scientifique. Unités Mixtes de Recherche; Francia

Oligodendrocyte precursor survival and differentiation requires chromatin remodeling by Chd7 and Chd8

International audienceOligodendrocyte precursor cells (OPCs) constitute the main proliferative cells in the adult brain, and deregulation of OPC proliferation-differentiation balance results in either glioma formation or defective adaptive (re)myelination. OPC differentiation requires significant genetic reprogramming, implicating chromatin remodeling. Mounting evidence indicates that chromatin remodelers play important roles during normal development and their mutations are associated with neurodevelopmental defects, with CHD7 haploinsuficiency being the cause of CHARGE syndrome and CHD8 being one of the strongest autism spectrum disorder (ASD) high-risk-associated genes. Herein, we report on uncharacterized functions of the chromatin remodelers Chd7 and Chd8 in OPCs. Their OPC-chromatin binding profile, combined with transcriptome and chromatin accessibility analyses of Chd7-deleted OPCs, demonstrates that Chd7 protects nonproliferative OPCs from apoptosis by chromatin closing and transcriptional repression of p53 Furthermore, Chd7 controls OPC differentiation through chromatin opening and transcriptional activation of key regulators, including Sox10, Nkx2.2, and Gpr17 However, Chd7 is dispensable for oligodendrocyte stage progression, consistent with Chd8 compensatory function, as suggested by their common chromatin-binding profiles and genetic interaction. Finally, CHD7 and CHD8 bind in OPCs to a majority of ASD risk-associated genes, suggesting an implication of oligodendrocyte lineage cells in ASD neurological defects. Our results thus offer new avenues to understand and modulate the CHD7 and CHD8 functions in normal development and disease

Progressive ataxia of Charolais cattle highlights a role of KIF1C in sustainable myelination.

Hereditary spastic paraplegias (HSPs) are clinically and genetically heterogeneous human neurodegenerative diseases. Amongst the identified genetic causes, mutations in genes encoding motor proteins such as kinesins have been involved in various HSP clinical isoforms. Mutations in KIF1C are responsible for autosomal recessive spastic paraplegia type 58 (SPG58) and spastic ataxia 2 (SPAX2). Bovines also develop neurodegenerative diseases, some of them having a genetic aetiology. Bovine progressive ataxia was first described in the Charolais breed in the early 1970s in England and further cases in this breed were subsequently reported worldwide. We can now report that progressive ataxia of Charolais cattle results from a homozygous single nucleotide polymorphism in the coding region of the KIF1C gene. In this study, we show that the mutation at the heterozygous state is associated with a better score for muscular development, explaining its balancing selection for several decades, and the resulting high frequency (13%) of the allele in the French Charolais breed. We demonstrate that the KIF1C bovine mutation leads to a functional knock-out, therefore mimicking mutations in humans affected by SPG58/SPAX2. The functional consequences of KIF1C loss of function in cattle were also histologically reevaluated. We showed by an immunochemistry approach that demyelinating plaques were due to altered oligodendrocyte membrane protrusion, and we highlight an abnormal accumulation of actin in the core of demyelinating plaques, which is normally concentrated at the leading edge of oligodendrocytes during axon wrapping. We also observed that the lesions were associated with abnormal extension of paranodal sections. Moreover, this model highlights the role of KIF1C protein in preserving the structural integrity and function of myelin, since the clinical signs and lesions arise in young-adult Charolais cattle. Finally, this model provides useful information for SPG58/SPAX2 disease and other demyelinating lesions

Imaging and multi-omics datasets converge to define different neural progenitor origins for ATRT-SHH subgroups

International audienceAbstract Atypical teratoid rhabdoid tumors (ATRT) are divided into MYC, TYR and SHH subgroups, suggesting diverse lineages of origin. Here, we investigate the imaging of human ATRT at diagnosis and the precise anatomic origin of brain tumors in the Rosa26-Cre ERT2 ::Smarcb1 flox/flox model. This cross-species analysis points to an extra-cerebral origin for MYC tumors. Additionally, we clearly distinguish SHH ATRT emerging from the cerebellar anterior lobe (CAL) from those emerging from the basal ganglia (BG) and intra-ventricular (IV) regions. Molecular characteristics point to the midbrain-hindbrain boundary as the origin of CAL SHH ATRT, and to the ganglionic eminence as the origin of BG/IV SHH ATRT. Single-cell RNA sequencing on SHH ATRT supports these hypotheses. Trajectory analyses suggest that SMARCB1 loss induces a de-differentiation process mediated by repressors of the neuronal program such as REST , ID and the NOTCH pathway

Variants detected by whole-genome sequencing of 3 animals, including 2 with progressive ataxia.

<p>Variants detected by whole-genome sequencing of 3 animals, including 2 with progressive ataxia.</p

<i>KIF1C</i> variant affects mRNA expression and leads to a functional knock-out.

<p>(A) Schematic diagram of the <i>KIF1C</i> gene in bovine sequence, located on chromosome 19, with the mutation indicated by an arrow. Primer pairs p1 and p2 (respectively amplifying <i>KIF1C</i> exons 1 to 11 and exons 13 to 20) are shown downstream of the diagram. RT-PCR from WT and affected bovine brains with p1 and p2 primer pairs demonstrated that <i>KIF1C</i> expression is modified in affected animals both in quantity–with mRNA decay–and quality (several transcripts in affected animals). <i>RPL13</i> (ribosomal protein L13) was used as a housekeeping gene. (B) Schematic diagram of <i>KIF1C</i> transcripts in affected bovine. The normal transcript bears the G>A mutation and leads to a mutated protein; the alternative transcript results from defective splicing and leads to exon 5 skipping. (C) Proteins were extracted from brains of WT and affected bovines, and from HeLa cells. Samples were analysed by immunoblotting with antibody against KIF1C proteins. No KIF1C protein was found in affected animals. WT, wild type; Aff, affected.</p