Publications by authors named "Mohamed Doulazmi"

33 Publications

Long-term effect of apomorphine infusion in advanced Parkinson's disease: a real-life study.

NPJ Parkinsons Dis 2021 Jun 11;7(1):50. Epub 2021 Jun 11.

Neurology Department, Pitié-Salpêtrière Hospital, AP-HP, Paris, France.

Long-term effects of continuous subcutaneous apomorphine infusion (CSAI) on health-related quality of life (HRQoL) and predictors of CSAI discontinuation are poorly known. Data from consecutive advanced Parkinson's disease patients treated in routine care were retrospectively collected over 24 months after CSAI initiation, with a focus on the 39-item Parkinson's disease questionnaire (PDQ-39). We determined predictors of CSAI discontinuation and HRQoL improvement using multiple regression analysis. Of the 110 subjects evaluated over a 2-year period, 35% discontinued CSAI. Of those who continued treatment, HRQoL remained stable with a sustained reduction in motor fluctuations. The observed effect on dyskinesias was mild and transient. Of note, patients with preexisting impulse control disorders showed an overall good tolerability. PDQ-39 was the only baseline predictor of HRQoL improvement after 2 years of treatment. The presence of dyskinesias, poorer psychological status, shorter disease duration, male sex, and worse OFF state were predictors of discontinuation. Best candidates for CSAI are patients with: (i) poor baseline HRQoL and (ii) marked motor fluctuations.
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http://dx.doi.org/10.1038/s41531-021-00194-7DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8196159PMC
June 2021

Clinical characteristics of sleep apnea in middle-old and oldest-old inpatients: symptoms and comorbidities.

Sleep Med 2021 06 16;82:179-185. Epub 2021 Apr 16.

Sorbonne Université, CNRS, UMR 8256 Biological Adaptation and Aging, F-75005, Paris, France; Assistance Publique - Hôpitaux de Paris (AP-HP), DHU FAST, Functional Explorations and Sleep Investigation Unit for the Older Patients, Charles Foix Hospital, Pitié-Salpêtrière-Charles Foix Group, F-94200, Ivry-sur-Seine, France; Sorbonne Université, UFR Médecine, F-75013, Paris, France. Electronic address:

Background: Obstructive sleep apnea (OSA) is prevalent in older adults but still underdiagnosed for many reasons, such as underreported symptoms, non-specific ones because of the comorbidities and polypharmacy, or the social belief of sleep problems as normal with aging.

Objectives: To identify salient symptoms and comorbidities associated with OSA, diagnosed by nocturnal respiratory polygraphy in geriatric inpatients.

Method: We conducted a retrospective, cross-sectional study in a sample of 102 geriatric inpatients from a French Geriatric University Hospital. We reviewed medical records to collect demographic, medical information including comorbidities, the geriatric cumulative illness rating scale (CIRS-G), subjective sleep-related symptoms and data of overnight level three portable sleep polygraphy recording.

Results: Among classic OSA symptoms, only excessive daytime sleepiness (p = 0.02) and nocturnal choking (p = 0.03) were more prevalent in older inpatients with OSA (n = 64) than in those without (n = 38). The prevalence of comorbidities and mean CIRS-G scores were not different between groups except for the lower prevalence of chronic obstructive pulmonary disease and the higher level of creatinine clearance in OSA patients. Multivariate analysis showed OSA was associated with excessive daytime sleepiness (OR = 2.83, p = 0.02) in symptoms-related model and with composite CIRS-G score (OR 1.26, p = 0.04) in comorbidities-related model.

Conclusions: Only excessive daytime sleepiness and comorbidity severity (composite CIRS-G score) were associated with the objective diagnosis of OSA, while other usual clinical OSA symptoms and comorbidities in geriatric inpatients were not. These findings emphasize the importance of excessive daytime sleepiness symptom, when reported in comorbid older patients, strongly suggesting OSA and requiring adequate nocturnal exploration.
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http://dx.doi.org/10.1016/j.sleep.2021.04.017DOI Listing
June 2021

Loss of floor plate Netrin-1 impairs midline crossing of corticospinal axons and leads to mirror movements.

Cell Rep 2021 Jan;34(3):108654

Sorbonne Université, CNRS, INSERM, Institut de Biologie Paris-Seine (IBPS), Neuroscience Paris-Seine (NPS), 75005 Paris, France. Electronic address:

In humans, execution of unimanual movements requires lateralized activation of the primary motor cortex, which then transmits the motor command to the contralateral hand through the crossed corticospinal tract (CST). Mutations in NTN1 alter motor control lateralization, leading to congenital mirror movements. To address the role of midline Netrin-1 on CST development and subsequent motor control, we analyze the morphological and functional consequences of floor plate Netrin-1 depletion in conditional knockout mice. We show that depletion of floor plate Netrin-1 in the brainstem critically disrupts CST midline crossing, whereas the other commissural systems are preserved. The only associated defect is an abnormal entry of CST axons within the inferior olive. Alteration of CST midline crossing results in functional ipsilateral projections and is associated with abnormal symmetric movements. Our study reveals the role of Netrin-1 in CST development and describes a mouse model recapitulating the characteristics of human congenital mirror movements.
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http://dx.doi.org/10.1016/j.celrep.2020.108654DOI Listing
January 2021

Primary cilium-dependent cAMP/PKA signaling at the centrosome regulates neuronal migration.

Sci Adv 2020 Sep 2;6(36). Epub 2020 Sep 2.

Sorbonne Université, CNRS UMR8246, Inserm U1130, Institut de Biologie Paris Seine (IBPS), Neuroscience Paris Seine (NPS), F-75005 Paris, France.

The primary cilium (PC) is a small centrosome-assembled organelle, protruding from the surface of most eukaryotic cells. It plays a key role in cell migration, but the underlying mechanisms are unknown. Here, we show that the PC regulates neuronal migration via cyclic adenosine 3'-5' monosphosphate (cAMP) production activating centrosomal protein kinase A (PKA). Biosensor live imaging revealed a periodic cAMP hotspot at the centrosome of embryonic, postnatal, and adult migrating neurons. Genetic ablation of the PC, or knockdown of ciliary adenylate cyclase 3, caused hotspot disappearance and migratory defects, with defective centrosome dynamics and altered nucleokinesis. Delocalization of PKA from the centrosome phenocopied the migratory defects. Our results show that the PC and centrosome form a single cAMP signaling unit dynamically regulating migration, further highlighting the centrosome as a signaling hub.
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http://dx.doi.org/10.1126/sciadv.aba3992DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7467704PMC
September 2020

Alternative polyadenylation produces multiple 3' untranslated regions of odorant receptor mRNAs in mouse olfactory sensory neurons.

BMC Genomics 2019 Jul 12;20(1):577. Epub 2019 Jul 12.

CNRS, INSERM, Institut de Biologie Paris Seine, Neuroscience Paris Seine, NPS, Sorbonne Université, F-75005, Paris, France.

Background: Odorant receptor genes constitute the largest gene family in mammalian genomes and this family has been extensively studied in several species, but to date far less attention has been paid to the characterization of their mRNA 3' untranslated regions (3'UTRs). Given the increasing importance of UTRs in the understanding of RNA metabolism, and the growing interest in alternative polyadenylation especially in the nervous system, we aimed at identifying the alternative isoforms of odorant receptor mRNAs generated through 3'UTR variation.

Results: We implemented a dedicated pipeline using IsoSCM instead of Cufflinks to analyze RNA-Seq data from whole olfactory mucosa of adult mice and obtained an extensive description of the 3'UTR isoforms of odorant receptor mRNAs. To validate our bioinformatics approach, we exhaustively analyzed the 3'UTR isoforms produced from 2 pilot genes, using molecular approaches including northern blot and RNA ligation mediated polyadenylation test. Comparison between datasets further validated the pipeline and confirmed the alternative polyadenylation patterns of odorant receptors. Qualitative and quantitative analyses of the annotated 3' regions demonstrate that 1) Odorant receptor 3'UTRs are longer than previously described in the literature; 2) More than 77% of odorant receptor mRNAs are subject to alternative polyadenylation, hence generating at least 2 detectable 3'UTR isoforms; 3) Splicing events in 3'UTRs are restricted to a limited subset of odorant receptor genes; and 4) Comparison between male and female data shows no sex-specific differences in odorant receptor 3'UTR isoforms.

Conclusions: We demonstrated for the first time that odorant receptor genes are extensively subject to alternative polyadenylation. This ground-breaking change to the landscape of 3'UTR isoforms of Olfr mRNAs opens new avenues for investigating their respective functions, especially during the differentiation of olfactory sensory neurons.
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http://dx.doi.org/10.1186/s12864-019-5927-3DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6624953PMC
July 2019

Descriptive analysis of the French NS-Park registry: Towards a nation-wide Parkinson's disease cohort?

Parkinsonism Relat Disord 2019 07 25;64:226-234. Epub 2019 Apr 25.

Sorbonne Université, Assistance Publique Hôpitaux de Paris, Institut du Cerveau et de la Moelle épinière, ICM, Inserm U 1127, CNRS UMR 7225, Department of Neurology, Hôpital Pitié-Salpêtrière, F-75013, Paris, France; Center for Interdisciplinary Research in Biology, Collège de France, INSERM U1050, CNRS UMR7241, Labex Memolife, Paris Sciences et Lettres, Paris, France; AP-HP, Department of Neurology, Hôpital Avicenne, Hôpitaux Universitaires de Paris - Seine Saint Denis, Bobigny, France. Electronic address:

Introduction: Parkinson's disease (PD) is the second most common neurodegenerative disorder after Alzheimer's. The French clinical research network for PD (NS-Park) has created a national patient registry to i)report medical activity of Parkinson Expert Centers (PECs) to the Ministry of Health, ii)facilitate PD patients pre-screening for clinical trials, iii) provide a source for pharmaco-epidemiology studies.

Objective: Assess the French Parkinsonian population at a nation-wide level and discover new clinical characteristics.

Methods: In this feasibility study, PECs prospectively collected clinical data in a standardized manner. The population main clinical characteristics are described, focusing on motor and non-motor symptoms and treatments, assessing its representativeness. By using an unbiased clustering with multiple correspondence analysis (MCA), we also investigate potential relationships between multiple variables like symptoms and treatments, as clues for future studies.

Results: Between 2012 and 2016, among 11,157 included parkinsonian syndromes, 9454 (85%) had PD. MCA identified various profiles depending on disease duration. Occurrences of motor complications, axial signs, cognitive disorders and Levodopa use increase over time. Neurovegetative symptoms, psychiatric disorders, sleep disturbances and impulse control disorders (ICDs) seem stable over time. As expected, ICDs were associated to dopaminergic agonist use but other associations, such as ICDs and sleep disturbances for instance, or anxiety and depression, were found.

Conclusions: Our results report one of the biggest PD registries ever reported and demonstrate the feasibility of implementing a nation-wide registry of PD patients in France, a potent tool for future longitudinal studies and clinical trials' population selection, and for pharmaco-epidemiology and cost-effectiveness studies.
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http://dx.doi.org/10.1016/j.parkreldis.2019.04.012DOI Listing
July 2019

Low-intensity electromagnetic fields induce human cryptochrome to modulate intracellular reactive oxygen species.

PLoS Biol 2018 10 2;16(10):e2006229. Epub 2018 Oct 2.

Sorbonne Université, CNRS Unit Biological Adaptation and Ageing, Photobiology Team, Paris, France.

Exposure to man-made electromagnetic fields (EMFs), which increasingly pollute our environment, have consequences for human health about which there is continuing ignorance and debate. Whereas there is considerable ongoing concern about their harmful effects, magnetic fields are at the same time being applied as therapeutic tools in regenerative medicine, oncology, orthopedics, and neurology. This paradox cannot be resolved until the cellular mechanisms underlying such effects are identified. Here, we show by biochemical and imaging experiments that exposure of mammalian cells to weak pulsed electromagnetic fields (PEMFs) stimulates rapid accumulation of reactive oxygen species (ROS), a potentially toxic metabolite with multiple roles in stress response and cellular ageing. Following exposure to PEMF, cell growth is slowed, and ROS-responsive genes are induced. These effects require the presence of cryptochrome, a putative magnetosensor that synthesizes ROS. We conclude that modulation of intracellular ROS via cryptochromes represents a general response to weak EMFs, which can account for either therapeutic or pathological effects depending on exposure. Clinically, our findings provide a rationale to optimize low field magnetic stimulation for novel therapeutic applications while warning against the possibility of harmful synergistic effects with environmental agents that further increase intracellular ROS.
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http://dx.doi.org/10.1371/journal.pbio.2006229DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6168118PMC
October 2018

Dysregulated Neurotransmission induces Trans-synaptic degeneration in reconstructed Neuronal Networks.

Sci Rep 2018 08 2;8(1):11596. Epub 2018 Aug 2.

CNRS UMR 8256, Biological Adaptation and Ageing, Paris, F-75005, France.

Increasing evidence suggests that pathological hallmarks of chronic degenerative syndromes progressively spread among interconnected brain areas in a disease-specific stereotyped pattern. Functional brain imaging from patients affected by various neurological syndromes such as traumatic brain injury and stroke indicates that the progression of such diseases follows functional connections, rather than simply spreading to structurally adjacent areas. Indeed, initial damage to a given brain area was shown to disrupt the communication in related brain networks. Using cortico-striatal neuronal networks reconstructed in a microfluidic environment, we investigated the role of glutamate signaling in activity-dependent neuronal survival and trans-synaptic degeneration processes. Using a variety of neuronal insults applied on cortical neurons, we demonstrate that acute injuries such as axonal trauma, focal ischemia, or alteration of neuronal rhythms, lead to glutamate-dependent striatal neuron dysfunction. Interestingly, focal pro-oxidant insults or chronic alteration of spontaneous cortical rhythms provoked dysfunction of distant striatal neurons through abnormal glutamate GluN2B-NMDAR-mediated signaling at cortico-striatal synapses. These results indicate that focal alteration of cortical functions can initiate spreading of dysfunction along neuronal pathways in the brain, reminiscent of diaschisis-like processes.
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http://dx.doi.org/10.1038/s41598-018-29918-1DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6072786PMC
August 2018

Health-Related Quality of Life Is Severely Affected in Primary Orthostatic Tremor.

Front Neurol 2017 15;8:747. Epub 2018 Jan 15.

Département de Neurologie, Groupe Hospitalier Pitié-Salpêtrière, Assistance Publique-Hôpitaux de Paris, Paris, France.

Background: Primary orthostatic tremor (POT) is a movement disorder characterized by unsteadiness upon standing still due to a tremor affecting the legs. It is a gradually progressive condition with limited treatment options. Impairments in health-related quality of life (HQoL) seem to far exceed the physical disability associated with the condition.

Methods: A multi-center, mixed-methodology study was undertaken to investigate 40 consecutive patients presenting with POT to four movement disorder centers in France. HQoL was investigated using eight quantitative scales and a qualitative study which employed semi-structured interviews. Qualitative data were analyzed with a combination of grounded-theory approach.

Results: Our results confirm that HQoL in POT is severely affected. Fear of falling was identified as the main predictor of HQoL. The qualitative arm of our study explored our initial results in greater depth and uncovered themes not identified by the quantitative approach.

Conclusion: Our results illustrate the huge potential of mixed methodology in identifying issues influencing HQoL in POT. Our work paves the way for enhanced patient care and improved HQoL in POT and is paradigmatic of this modern approach for investigating HQoL issues in chronic neurological disorders.
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http://dx.doi.org/10.3389/fneur.2017.00747DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5775514PMC
January 2018

A randomized, controlled, double-blind, crossover trial of triheptanoin in alternating hemiplegia of childhood.

Orphanet J Rare Dis 2017 10 2;12(1):160. Epub 2017 Oct 2.

Université de la Sorbonne, UPMC Paris 06, UMR S 1127, Inserm U 1127, CNRS UMR 7225, Institut du Cerveau et de la Moëlle, F-75013, Paris, France.

Background: Based on the hypothesis of a brain energy deficit, we investigated the safety and efficacy of triheptanoin on paroxysmal episodes in patients with alternating hemiplegia of childhood due to ATP1A3 mutations.

Methods: We conducted a randomized, double-blind, placebo-controlled crossover study of triheptanoin, at a target dose corresponding to 30% of daily calorie intake, in ten patients with alternating hemiplegia of childhood due to ATP1A3 mutations. Each treatment period consisted of a 12-week fixed-dose phase, separated by a 4-week washout period. The primary outcome was the total number of paroxysmal events. Secondary outcomes included the number of paroxysmal motor-epileptic events; a composite score taking into account the number, severity and duration of paroxysmal events; interictal neurological manifestations; the clinical global impression-improvement scale (CGI-I); and safety parameters. The paired non-parametric Wilcoxon test was used to analyze treatment effects.

Results: In an intention-to-treat analysis, triheptanoin failed to reduce the total number of paroxysmal events (p = 0.646), including motor-epileptic events (p = 0.585), or the composite score (p = 0.059). CGI-I score did not differ between triheptanoin and placebo periods. Triheptanoin was well tolerated.

Conclusions: Triheptanoin does not prevent paroxysmal events in Alternating hemiplegia of childhood. We show the feasibility of a randomized placebo-controlled trial in this setting.

Trial Registration: The study has been registered with clinicaltrials.gov ( NCT002408354 ) the 03/24/2015.
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http://dx.doi.org/10.1186/s13023-017-0713-2DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5625655PMC
October 2017

Mutations in the netrin-1 gene cause congenital mirror movements.

J Clin Invest 2017 Nov 25;127(11):3923-3936. Epub 2017 Sep 25.

Pathology Department, Dunedin School of Medicine, University of Otago, Dunedin, New Zealand.

Netrin-1 is a secreted protein that was first identified 20 years ago as an axon guidance molecule that regulates midline crossing in the CNS. It plays critical roles in various tissues throughout development and is implicated in tumorigenesis and inflammation in adulthood. Despite extensive studies, no inherited human disease has been directly associated with mutations in NTN1, the gene coding for netrin-1. Here, we have identified 3 mutations in exon 7 of NTN1 in 2 unrelated families and 1 sporadic case with isolated congenital mirror movements (CMM), a disorder characterized by involuntary movements of one hand that mirror intentional movements of the opposite hand. Given the diverse roles of netrin-1, the absence of manifestations other than CMM in NTN1 mutation carriers was unexpected. Using multimodal approaches, we discovered that the anatomy of the corticospinal tract (CST) is abnormal in patients with NTN1-mutant CMM. When expressed in HEK293 or stable HeLa cells, the 3 mutated netrin-1 proteins were almost exclusively detected in the intracellular compartment, contrary to WT netrin-1, which is detected in both intracellular and extracellular compartments. Since netrin-1 is a diffusible extracellular cue, the pathophysiology likely involves its loss of function and subsequent disruption of axon guidance, resulting in abnormal decussation of the CST.
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http://dx.doi.org/10.1172/JCI95442DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5663368PMC
November 2017

Relationship between sleep parameters, insulin resistance and age-adjusted insulin like growth factor-1 score in non diabetic older patients.

PLoS One 2017 6;12(4):e0174876. Epub 2017 Apr 6.

Assistance Publique-Hôpitaux de Paris (APHP), DHU FAST, Functional Exploration Unit of older patients, Groupe hospitalier Pitié-Salpêtrière-Charles Foix, Paris, France.

Background: Sleep complaints are prevalent in older patients. Sleepiness, short or long sleep duration and obstructive sleep apnea (OSA) are associated with insulin resistance (IR). These parameters have not yet been considered together in the same study exploring the possible association between IR and sleep in older patients. IR is involved in cardiovascular and metabolic diseases, pathologies which are highly prevalent in older patients. Here we assess, in older non-diabetic patients with sleep complaints, the associations between IR and sleep parameters objectively recorded by polysomnography (PSG) rather than self-report. The Growth Hormone/Insulin like growth factor-1 axis could play a role in the development of IR during sleep disorders. The second objective of this study was to analyze the association between sleep parameters and age-adjusted IGF-1 score, which could explain the association between OSA and IR.

Methods: 72 non-diabetic older patients, mean age 74.5 ± 7.8 years, were included in this observational study. We evaluated anthropometric measures, subjective and objective sleepiness, polysomnography, Homeostatic Model Assessment for IR (HOMA-IR) and age-adjusted IGF-1 score. A multivariate regression was used to determine factors associated with HOMA-IR.

Results: The 47 OSA patients were over-weight but not obese and had higher IR than the non-OSA patients. In multilinear regression analysis, apnea-hypopnea index was independently associated with IR after adjustment for several confounding factors. Neither IGF-1 level nor IGF-1 score were different in the two groups.

Conclusions: We demonstrate that in non-diabetic older patients with sleep complaints, OSA is independently associated with IR, regardless of anthropometric measurements and sleep parameters (sleep duration/sleepiness/arousals). Targeting OSA to reduce IR could be useful in the elderly, although further exploration is required.
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http://journals.plos.org/plosone/article?id=10.1371/journal.pone.0174876PLOS
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5383056PMC
September 2017

Non cell-autonomous role of DCC in the guidance of the corticospinal tract at the midline.

Sci Rep 2017 03 24;7(1):410. Epub 2017 Mar 24.

Sorbonne Universités, UPMC Univ Paris 06, INSERM U 1127, CNRS UMR 7225, Institut du Cerveau et de la Moelle épinière, F-75013, Paris, France.

DCC, a NETRIN-1 receptor, is considered as a cell-autonomous regulator for midline guidance of many commissural populations in the central nervous system. The corticospinal tract (CST), the principal motor pathway for voluntary movements, crosses the anatomic midline at the pyramidal decussation. CST fails to cross the midline in Kanga mice expressing a truncated DCC protein. Humans with heterozygous DCC mutations have congenital mirror movements (CMM). As CMM has been associated, in some cases, with malformations of the pyramidal decussation, DCC might also be involved in this process in human. Here, we investigated the role of DCC in CST midline crossing both in human and mice. First, we demonstrate by multimodal approaches, that patients with CMM due to DCC mutations have an increased proportion of ipsilateral CST projections. Second, we show that in contrast to Kanga mice, the anatomy of the CST is not altered in mice with a deletion of DCC in the CST. Altogether, these results indicate that DCC controls CST midline crossing in both humans and mice, and that this process is non cell-autonomous in mice. Our data unravel a new level of complexity in the role of DCC in CST guidance at the midline.
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http://dx.doi.org/10.1038/s41598-017-00514-zDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5428661PMC
March 2017

BFPTool: a software tool for analysis of Biomembrane Force Probe experiments.

BMC Biophys 2017 13;10. Epub 2017 Feb 13.

Institute of Physiology, Czech Academy of Sciences, Vídeňská 1083, Prague, 14220 Czech Republic.

Background: The Biomembrane Force Probe is an approachable experimental technique commonly used for single-molecule force spectroscopy and experiments on biological interfaces. The technique operates in the range of forces from 0.1 pN to 1000 pN. Experiments are typically repeated many times, conditions are often not optimal, the captured video can be unstable and lose focus; this makes efficient analysis challenging, while out-of-the-box non-proprietary solutions are not freely available.

Results: This dedicated tool was developed to integrate and simplify the image processing and analysis of videomicroscopy recordings from BFP experiments. A novel processing feature, allowing the tracking of the pipette, was incorporated to address a limitation of preceding methods. Emphasis was placed on versatility and comprehensible user interface implemented in a graphical form.

Conclusions: An integrated analytical tool was implemented to provide a faster, simpler and more convenient way to process and analyse BFP experiments.
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http://dx.doi.org/10.1186/s13628-016-0033-2DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5304404PMC
February 2017

New insights into the regulatory function of CYFIP1 in the context of WAVE- and FMRP-containing complexes.

Dis Model Mech 2017 04 9;10(4):463-474. Epub 2017 Feb 9.

Université Côte d'Azur, Nice, France

Cytoplasmic FMRP interacting protein 1 () is a candidate gene for intellectual disability (ID), autism, schizophrenia and epilepsy. It is a member of a family of proteins that is highly conserved during evolution, sharing high homology with its homolog, dCYFIP. CYFIP1 interacts with the Fragile X mental retardation protein (FMRP, encoded by the gene), whose absence causes Fragile X syndrome, and with the translation initiation factor eIF4E. It is a member of the WAVE regulatory complex (WRC), thus representing a link between translational regulation and the actin cytoskeleton. Here, we present data showing a correlation between mRNA levels of and other members of the WRC. This suggests a tight regulation of the levels of the WRC members, not only by post-translational mechanisms, as previously hypothesized. Moreover, we studied the impact of loss of function of both CYFIP1 and FMRP on neuronal growth and differentiation in two animal models - fly and mouse. We show that these two proteins antagonize each other's function not only during neuromuscular junction growth in the fly but also during new neuronal differentiation in the olfactory bulb of adult mice. Mechanistically, FMRP and CYFIP1 modulate mTor signaling in an antagonistic manner, likely via independent pathways, supporting the results obtained in mouse as well as in fly at the morphological level. Collectively, our results illustrate a new model to explain the cellular roles of FMRP and CYFIP1 and the molecular significance of their interaction.
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http://dx.doi.org/10.1242/dmm.025809DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5399562PMC
April 2017

The intellectual disability protein PAK3 regulates oligodendrocyte precursor cell differentiation.

Neurobiol Dis 2017 02 6;98:137-148. Epub 2016 Dec 6.

Sorbonne Universités, UPMC Univ Paris 06, INSERM, CNRS, Institut de Biologie Paris Seine, Neuroscience Paris Seine, F-75005 Paris, France; Sorbonne Universités, UPMC Univ Paris 06, INSERM U 1127, CNRS UMR 7225, Institut du Cerveau et de la Moelle épinière, F-75013 Paris, France. Electronic address:

Oligodendrocyte and myelin deficits have been reported in mental/psychiatric diseases. The p21-activated kinase 3 (PAK3), a serine/threonine kinase, whose activity is stimulated by the binding of active Rac and Cdc42 GTPases is affected in these pathologies. Indeed, many mutations of Pak3 gene have been described in non-syndromic intellectual disability diseases. Pak3 is expressed mainly in the brain where its role has been investigated in neurons but not in glial cells. Here, we showed that PAK3 is highly expressed in oligodendrocyte precursors (OPCs) and its expression decreases in mature oligodendrocytes. In the developing white matter of the Pak3 knockout mice, we found defects of oligodendrocyte differentiation in the corpus callosum and to a lesser extent in the anterior commissure, which were compensated at the adult stage. In vitro experiments in OPC cultures, derived from Pak3 knockout and wild type brains, support a developmental and cell-autonomous role for PAK3 in regulating OPC differentiation into mature oligodendrocytes. Moreover, we did not detect any obvious alterations of the proliferation or migration of Pak3 null OPCs compared to wild type. Overall, our data highlight PAK3 as a new regulator of OPC differentiation.
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http://dx.doi.org/10.1016/j.nbd.2016.12.004DOI Listing
February 2017

Selective Effects of PDE10A Inhibitors on Striatopallidal Neurons Require Phosphatase Inhibition by DARPP-32

eNeuro 2015 Jul-Aug;2(4). Epub 2015 Aug 31.

CNRS, UMR8256 "Biological Adaptation and Ageing", Institut de Biologie Paris-Seine (IBPS) , F-75005 Paris, France ; Université Pierre et Marie Curie (UPMC, Paris 6), Sorbonne Universités , Paris, F-75005, France.

Type 10A phosphodiesterase (PDE10A) is highly expressed in the striatum, in striatonigral and striatopallidal medium-sized spiny neurons (MSNs), which express D1 and D2 dopamine receptors, respectively. PDE10A inhibitors have pharmacological and behavioral effects suggesting an antipsychotic profile, but the cellular bases of these effects are unclear. We analyzed the effects of PDE10A inhibition in vivo by immunohistochemistry, and imaged cAMP, cAMP-dependent protein kinase A (PKA), and cGMP signals with biosensors in mouse brain slices. PDE10A inhibition in mouse striatal slices produced a steady-state increase in intracellular cAMP concentration in D1 and D2 MSNs, demonstrating that PDE10A regulates basal cAMP levels. Surprisingly, the PKA-dependent AKAR3 phosphorylation signal was strong in D2 MSNs, whereas D1 MSNs remained unresponsive. This effect was also observed in adult mice in vivo since PDE10A inhibition increased phospho-histone H3 immunoreactivity selectively in D2 MSNs in the dorsomedial striatum. The PKA-dependent effects in D2 MSNs were prevented in brain slices and in vivo by mutation of the PKA-regulated phosphorylation site of 32 kDa dopamine- and cAMP-regulated phosphoprotein (DARPP-32), which is required for protein phosphatase-1 inhibition. These data highlight differences in the integration of the cAMP signal in D1 and D2 MSNs, resulting from stronger inhibition of protein phosphatase-1 by DARPP-32 in D2 MSNs than in D1 MSNs. This study shows that PDE10A inhibitors share with antipsychotic medications the property of activating preferentially PKA-dependent signaling in D2 MSNs.
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http://dx.doi.org/10.1523/ENEURO.0060-15.2015DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4596023PMC
October 2015

Interleukin-10 Production in Response to Amyloid-β Differs between Slow and Fast Decliners in Patients with Alzheimer's Disease.

J Alzheimers Dis 2015 ;46(4):837-42

ImmunoClin Ltd, London, UK.

We investigated IL-10 and IL-6 production in amyloid-β (Aβ) stimulated peripheral blood mononuclear cells (PBMCs) in twenty Alzheimer's disease (AD) patients with slow progression, eleven with fast progression, and twenty age-matched controls. Promoter polymorphisms in IL-10 (position -592, -819, -1082), IL-6 (-174), transforming growth factor-β1 (TGF-β1) (-10, -25), interferon-γ (IFN-γ) (-874), and tumor necrosis factor-α (TNF-α) (-308) genes were analyzed. IL-10 production after Aβ stimulation was high in PBMCs from slow decliners and almost completely abrogated in fast decliners. Association between AA IFN-γ low-producing genotype and fast progression was demonstrated. Investigations in a larger sample will clarify these findings.
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http://dx.doi.org/10.3233/JAD-142832DOI Listing
June 2016

Leukocyte Telomere Length in Alzheimer's Disease Patients with a Different Rate of Progression.

J Alzheimers Dis 2015 ;46(3):761-9

Geriatric Unit, Department of Medical Sciences and Community Health, University of Milan, Milan, Italy.

Background: Age and short leukocyte telomeres have been associated with a higher risk of Alzheimer's disease (AD). Inflammation is involved in AD and it is suggested that anti-inflammatory interleukin-10 (IL-10) may partly antagonize these processes.

Objective: The aim is to correlate telomere length (TL) in peripheral blood mononuclear cells (PBMC) from patients with AD to disease progression rate. Moreover, we evaluated whether TL was associated with IL-10 production by unstimulated or amyloid-β (Aβ)-stimulated PBMC.

Methods: We enrolled 31 late-onset AD and 20 age-matched healthy elderly (HE). After a two-year follow-up period, patients were retrospectively evaluated as slow-progressing (ADS) (Mini Mental State Examination (MMSE) decline over the two years of follow-up ≤3 points) or fast progressing AD (ADF) (MMSE decline ≥5 points). TL was measured by flow cytometry and in vitro IL-10 production by enzyme-linked immunosorbent assay.

Results: TL (mean±SD) for HE, ADS, and ADF was 2.3±0.1, 2.0±0.1, and 2.5±0.1 Kb, respectively. ADS showed a shorter TL compared to HE (p = 0.034) and to ADF (p = 0.005). MMSE decline correlated with TL in AD (R2 = 0.284; p = 0.008). We found a significant difference in IL-10 production between unstimulated and Aβ-stimulated PBMC from ADS (40.7±13.7 versus 59.0±27.0; p = 0.004) but not from ADF (39.7±14.4 versus 42.2±22.4). HE showed a trend toward significance (47.1±25.4 versus 55.3±27.9; p = 0.10).

Conclusion: PBMC from ADF may be characterized by an impaired response induced by Aβ and by a reduced proliferative response responsible for the longer telomeres. TL might be a contributing factor in predicting the rate of AD progression.
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http://dx.doi.org/10.3233/JAD-142808DOI Listing
June 2016

Fragile X Mental Retardation Protein and Dendritic Local Translation of the Alpha Subunit of the Calcium/Calmodulin-Dependent Kinase II Messenger RNA Are Required for the Structural Plasticity Underlying Olfactory Learning.

Biol Psychiatry 2016 07 7;80(2):149-159. Epub 2015 Aug 7.

Sorbonne Universités, Université Pierre et Marie Curie Univ Paris 06, Centre National de la Recherche Scientifique UMR8246, INSERM U1130, IBPS, Neuroscience Paris Seine, France; Sorbonne Paris Cité, Université Paris Diderot-Paris 7. Electronic address:

Background: In the adult brain, structural plasticity allowing gain or loss of synapses remodels circuits to support learning. In fragile X syndrome, the absence of fragile X mental retardation protein (FMRP) leads to defects in plasticity and learning deficits. FMRP is a master regulator of local translation but its implication in learning-induced structural plasticity is unknown.

Methods: Using an olfactory learning task requiring adult-born olfactory bulb neurons and cell-specific ablation of FMRP, we investigated whether learning shapes adult-born neuron morphology during their synaptic integration and its dependence on FMRP. We used alpha subunit of the calcium/calmodulin-dependent kinase II (αCaMKII) mutant mice with altered dendritic localization of αCaMKII messenger RNA, as well as a reporter of αCaMKII local translation to investigate the role of this FMRP messenger RNA target in learning-dependent structural plasticity.

Results: Learning induces profound changes in dendritic architecture and spine morphology of adult-born neurons that are prevented by ablation of FMRP in adult-born neurons and rescued by an metabotropic glutamate receptor 5 antagonist. Moreover, dendritically translated αCaMKII is necessary for learning and associated structural modifications and learning triggers an FMRP-dependent increase of αCaMKII dendritic translation in adult-born neurons.

Conclusions: Our results strongly suggest that FMRP mediates structural plasticity of olfactory bulb adult-born neurons to support olfactory learning through αCaMKII local translation. This reveals a new role for FMRP-regulated dendritic local translation in learning-induced structural plasticity. This might be of clinical relevance for the understanding of critical periods disruption in autism spectrum disorder patients, among which fragile X syndrome is the primary monogenic cause.
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http://dx.doi.org/10.1016/j.biopsych.2015.07.023DOI Listing
July 2016

The RhoGEF DOCK10 is essential for dendritic spine morphogenesis.

Mol Biol Cell 2015 Jun 7;26(11):2112-27. Epub 2015 Apr 7.

Centre de Recherche en Biochimie Macromoléculaire, CNRS-UMR 5237, Université de Montpellier, 34293 Montpellier, France

By regulating actin cytoskeleton dynamics, Rho GTPases and their activators RhoGEFs are implicated in various aspects of neuronal differentiation, including dendritogenesis and synaptogenesis. Purkinje cells (PCs) of the cerebellum, by developing spectacular dendrites covered with spines, represent an attractive model system in which to decipher the molecular signaling underlying these processes. To identify novel regulators of dendritic spine morphogenesis among members of the poorly characterized DOCK family of RhoGEFs, we performed gene expression profiling of fluorescence-activated cell sorting (FACS)-purified murine PCs at various stages of their postnatal differentiation. We found a strong increase in the expression of the Cdc42-specific GEF DOCK10. Depleting DOCK10 in organotypic cerebellar cultures resulted in dramatic dendritic spine defects in PCs. Accordingly, in mouse hippocampal neurons, depletion of DOCK10 or expression of a DOCK10 GEF-dead mutant led to a strong decrease in spine density and size. Conversely, overexpression of DOCK10 led to increased spine formation. We show that DOCK10 function in spinogenesis is mediated mainly by Cdc42 and its downstream effectors N-WASP and PAK3, although DOCK10 is also able to activate Rac1. Our global approach thus identifies an unprecedented function for DOCK10 as a novel regulator of dendritic spine morphogenesis via a Cdc42-mediated pathway.
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http://dx.doi.org/10.1091/mbc.E14-08-1310DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4472020PMC
June 2015

Mature Purkinje cells require the retinoic acid-related orphan receptor-α (RORα) to maintain climbing fiber mono-innervation and other adult characteristics.

J Neurosci 2013 May;33(22):9546-62

UPMC Université Paris 06, UMR 7102, 75005 Paris, France.

Neuronal maturation during development is a multistep process regulated by transcription factors. The transcription factor RORα (retinoic acid-related orphan receptor α) is necessary for early Purkinje cell (PC) maturation but is also expressed throughout adulthood. To identify the role of RORα in mature PCs, we used Cre-lox mouse genetic tools in vivo that delete it specifically from PCs between postnatal days 10-21. Up to 14 d of age, differences between mutant and control PCs were not detectable: both were mono-innervated by climbing fibers (CFs) extending along their well-developed dendrites with spiny branchlets. By week 4, mutant mice were ataxic, some PCs had died, and remaining PC soma and dendrites were atrophic, with almost complete disappearance of spiny branchlets. The innervation pattern of surviving RORα-deleted PCs was abnormal with several immature characteristics. Notably, multiple functional CF innervation was reestablished on these mature PCs, simultaneously with the relocation of CF contacts to the PC soma and their stem dendrite. This morphological modification of CF contacts could be induced even later, using lentivirus-mediated depletion of rora from adult PCs. These data show that the late postnatal expression of RORα cell-autonomously regulates the maintenance of PC dendritic complexity, and the CF innervation status of the PC (dendritic vs somatic contacts, and mono-innervation vs multi-innervation). Thus, the differentiation state of adult neurons is under the control of transcription factors; and in their absence, adult neurons lose their mature characteristics and acquire some characteristics of an earlier developmental stage.
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http://dx.doi.org/10.1523/JNEUROSCI.2977-12.2013DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6618556PMC
May 2013

Aging-related episodic memory decline: are emotions the key?

Front Behav Neurosci 2013 1;7. Epub 2013 Feb 1.

Neurobiologie des Processus Adaptatifs, UMR 7102, Université Pierre et Marie Curie, Paris 6 Paris, France ; CNRS, UMR 7102 Paris, France ; Institut de la longévité, AP-HP Hôpital Charles Foix, Ivry-sur-Seine Paris, France.

Episodic memory refers to the recollection of personal experiences that contain information on what has happened and also where and when these events took place. Episodic memory function is extremely sensitive to cerebral aging and neurodegerative diseases. We examined episodic memory performance with a novel test in young (N = 17, age: 21-45), middle-aged (N = 16, age: 48-62) and aged but otherwise healthy participants (N = 8, age: 71-83) along with measurements of trait and state anxiety. As expected we found significantly impaired episodic memory performance in the aged group as compared to the young group. The aged group also showed impaired working memory performance as well as significantly decreased levels of trait anxiety. No significant correlation between the total episodic memory and trait or state anxiety scores was found. The present results show an age-dependent episodic memory decline along with lower trait anxiety in the aged group. Yet, it still remains to be determined whether this difference in anxiety is related to the impaired episodic memory performance in the aged group.
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http://dx.doi.org/10.3389/fnbeh.2013.00002DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3561617PMC
February 2013

Purkinje cell maturation participates in the control of oligodendrocyte differentiation: role of sonic hedgehog and vitronectin.

PLoS One 2012 14;7(11):e49015. Epub 2012 Nov 14.

Neurobiologie des Processus Adaptatif, Université Pierre et Marie Curie (UPMC Univ Paris 06), Paris, France.

Oligodendrocyte differentiation is temporally regulated during development by multiple factors. Here, we investigated whether the timing of oligodendrocyte differentiation might be controlled by neuronal differentiation in cerebellar organotypic cultures. In these cultures, the slices taken from newborn mice show very few oligodendrocytes during the first week of culture (immature slices) whereas their number increases importantly during the second week (mature slices). First, we showed that mature cerebellar slices or their conditioned media stimulated oligodendrocyte differentiation in immature slices thus demonstrating the existence of diffusible factors controlling oligodendrocyte differentiation. Using conditioned media from different models of slice culture in which the number of Purkinje cells varies drastically, we showed that the effects of these differentiating factors were proportional to the number of Purkinje cells. To identify these diffusible factors, we first performed a transcriptome analysis with an Affymetrix array for cerebellar cortex and then real-time quantitative PCR on mRNAs extracted from fluorescent flow cytometry sorted (FACS) Purkinje cells of L7-GFP transgenic mice at different ages. These analyses revealed that during postnatal maturation, Purkinje cells down-regulate Sonic Hedgehog and up-regulate vitronectin. Then, we showed that Sonic Hedgehog stimulates the proliferation of oligodendrocyte precursor cells and inhibits their differentiation. In contrast, vitronectin stimulates oligodendrocyte differentiation, whereas its inhibition with blocking antibodies abolishes the conditioned media effects. Altogether, these results suggest that Purkinje cells participate in controlling the timing of oligodendrocyte differentiation in the cerebellum through the developmentally regulated expression of diffusible molecules such as Sonic Hedgehog and vitronectin.
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http://journals.plos.org/plosone/article?id=10.1371/journal.pone.0049015PLOS
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3498367PMC
May 2013

Thyroid hormone triggers the developmental loss of axonal regenerative capacity via thyroid hormone receptor α1 and krüppel-like factor 9 in Purkinje cells.

Proc Natl Acad Sci U S A 2012 Aug 13;109(35):14206-11. Epub 2012 Aug 13.

Université Pierre et Marie Curie (UPMC) Paris 06, Unité Mixte de Recherche 7102, 75005 Paris, France.

Neurons in the CNS of higher vertebrates lose their ability to regenerate their axons at a stage of development that coincides with peak circulating thyroid hormone (T(3)) levels. Here, we examined whether this peak in T(3) is involved in the loss of axonal regenerative capacity in Purkinje cells (PCs). This event occurs at the end of the first postnatal week in mice. Using organotypic culture, we found that the loss of axon regenerative capacity was triggered prematurely by early exposure of mouse PCs to T(3), whereas it was delayed in the absence of T(3). Analysis of mutant mice showed that this effect was mainly mediated by the T(3) receptor α1. Using gain- and loss-of-function approaches, we also showed that Krüppel-like factor 9 was a key mediator of this effect of T(3). These results indicate that the sudden physiological increase in T(3) during development is involved in the onset of the loss of axon regenerative capacity in PCs. This loss of regenerative capacity might be part of the general program triggered by T(3) throughout the body, which adapts the animal to its postnatal environment.
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http://dx.doi.org/10.1073/pnas.1119853109DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3435228PMC
August 2012

Specific inhibition of the JNK pathway promotes locomotor recovery and neuroprotection after mouse spinal cord injury.

Neurobiol Dis 2012 Jun 9;46(3):710-21. Epub 2012 Mar 9.

UPMC Univ Paris 06, UMR 7102, Paris, France.

Limiting the development of secondary damage represents one of the major goals of neuroprotective therapies after spinal cord injury. Here, we demonstrate that specific JNK inhibition via a single intraperitoneal injection of the cell permeable peptide D-JNKI1 6h after lesion improves locomotor recovery assessed by both the footprint and the BMS tests up to 4 months post-injury in mice. JNK inhibition prevents c-jun phosphorylation and caspase-3 cleavage, has neuroprotective effects and results in an increased sparing of white matter at the lesion site. Lastly, D-JNKI1 treated animals show a lower increase of erythrocyte extravasation and blood brain barrier permeability, thus indicating protection of the vascular system. In total, these results clearly point out JNK inhibition as a promising neuroprotective strategy for preventing the evolution of secondary damage after spinal cord injury.
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http://dx.doi.org/10.1016/j.nbd.2012.03.014DOI Listing
June 2012

Age-related Purkinje cell death is steroid dependent: RORα haplo-insufficiency impairs plasma and cerebellar steroids and Purkinje cell survival.

Age (Dordr) 2011 Dec 11;33(4):565-78. Epub 2011 Jan 11.

UMR Neurobiologie des Processus Adaptatifs, UPMC Univ Paris, France.

A major problem of ageing is progressive impairment of neuronal function and ultimately cell death. Since sex steroids are neuroprotective, their decrease with age may underlie age-related neuronal degeneration. To test this, we examined Purkinje cell numbers, plasma sex steroids and cerebellar neurosteroid concentrations during normal ageing (wild-type mice, WT), in our model of precocious ageing (Rora(+/sg), heterozygous staggerer mice in which expression of the neuroprotective factor RORα is disrupted) and after long-term hormone insufficiency (WT post-gonadectomy). During normal ageing (WT), circulating sex steroids declined prior to or in parallel with Purkinje cell loss, which began at 18 months of age. Although Purkinje cell death was advanced in WT long-term steroid deficiency, this premature neuronal loss did not begin until 9 months, indicating that vulnerability to sex steroid deficiency is a phenomenon of ageing Purkinje neurons. In precocious ageing (Rora(+/sg)), circulating sex steroids decreased prematurely, in conjunction with marked Purkinje cell death from 9 months. Although Rora(+/sg) Purkinje cells are vulnerable through their RORα haplo-insufficiency, it is only as they age (after 9 months) that sex steroid failure becomes critical. Finally, cerebellar neurosteroids did not decrease with age in either genotype or gender; but were profoundly reduced by 3 months in male Rora(+/sg) cerebella, which may contribute to the fragility of their Purkinje neurons. These data suggest that ageing Purkinje cells are maintained by circulating sex steroids, rather than local neurosteroids, and that in Rora(+/sg) their age-related death is advanced by premature sex steroid loss induced by RORα haplo-insufficiency.
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http://dx.doi.org/10.1007/s11357-010-9203-3DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3220403PMC
December 2011

RORalpha, a pivotal nuclear receptor for Purkinje neuron survival and differentiation: from development to ageing.

Cerebellum 2006 ;5(2):97-104

Université Pierre et Marie Curie-Paris6, UMR 7102 - Neurobiologie des Processus Adaptatifs (NPA): CNRS, UMR 7102-NPA, 9, quai St-Bernard, Paris, F-75005, France.

RORalpha (Retinoid-related Orphan Receptor) is a transcription factor belonging to the superfamily of nuclear receptors. The spontaneous staggerer (sg) mutation, which consists of a deletion in the Rora gene, has been shown to cause the loss of function of the RORalpha protein. The total loss of RORalpha expression leads to cerebellar developmental defects, particularly to a dramatic decreased survival of Purkinje cells and an early block in the differentiation process. This review focuses on recent studies which position RORalpha as a pivotal factor controlling Purkinje cell survival and differentiation, from development to ageing.
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http://dx.doi.org/10.1080/14734220600750184DOI Listing
September 2006