Jean-Pierre Julien - Academia.edu (original) (raw)

Papers by Jean-Pierre Julien

médecine/sciences, 2008

Le cytosquelette est composé de 3 types de fibres de diamètre différent. Les plus grosses (25 nm)... more Le cytosquelette est composé de 3 types de fibres de diamètre différent. Les plus grosses (25 nm) sont les microtubules formés par la polymérisation/dépolymérisation de dimères d'α-et de β-tubuline à partir du centrosome. Dans les axones des neurones matures, ces microtubules sont stabilisés par des protéines associées aux microtubules (MAP) telles que Tau. Ces microtubules axonaux sont polarisés : ils comportent une extrémité positive de β-tubuline exposée à l'extérieur et une extrémité négative d'α-tubuline orientée vers le centre de la cellule. À l'inverse, les microtubules dendritiques ne sont pas polarisés. Les microfilaments d'actine sont de petit diamètre (6 nm), ils sont eux aussi hautement dynamiques. Ils participent à la croissance cellulaire. Enfin, des filaments de taille intermédiaire (10 nm) complètent l'architecture du cytosquelette. Il s'agit majoritairement des neurofilaments (NF) situés au sein des axones moteurs. Ils sont formés par l'association de 3 sous-unités : NF-L (chaîne légère), NF-M (chaîne moyenne) et NF-H (chaîne lourde).

Cell Death & Differentiation, 2002

The discovery of cell cycle regulators has directed cell research into uncharted territory. In di... more The discovery of cell cycle regulators has directed cell research into uncharted territory. In dividing cells, cell cycleassociated protein kinases, which are referred to as cyclindependent-kinases (Cdks), regulate proliferation, differentiation, senescence and apoptosis. In contrast, all Cdks in postmitotic neurons, with the notable exception of Cdk5, are silenced. Surprisingly, misregulation of Cdks occurs in neurons in a wide diversity of neurological disorders, including Alzheimer's disease, Parkinson's disease and amyotrophic lateral sclerosis. Ectopic expression of these proteins in neurons potently induces cell death with hallmarks of apoptosis. Deregulation of the unique, cell cycle-unrelated Cdk5 by its truncated co-activator, p25 and p29, contributes to neurodegeneration by altering the phosphorylation state of non-membrane-associated proteins and possibly through the induction of cell cycle proteins. On the other hand, cycling Cdks such as Cdk2, Cdk4 and Cdk6, initiate death pathways by derepressing E2F-1/Rb-dependent transcription at the neuronal G1/S checkpoint. Thus, Cdk5 and cycling Cdks may have little in common in the healthy CNS, but they likely conspire in leading neurons to their demise.

Journal of Cell Biology, 1999

Peripherin, a type III intermediate filament (IF) protein, upregulated by injury and inflammatory... more Peripherin, a type III intermediate filament (IF) protein, upregulated by injury and inflammatory cytokines, is a component of IF inclusion bodies associated with degenerating motor neurons in sporadic amyotrophic lateral sclerosis (ALS). We report here that sustained overexpression of wild-type peripherin in mice provokes massive and selective degeneration of motor axons during aging. Remarkably, the onset of peripherin-mediated disease was precipitated by a deficiency of neurofilament light (NF-L) protein, a phenomenon associated with sporadic ALS. In NF-L null mice, the overexpression of peripherin led to early- onset formation of IF inclusions and to the selective death of spinal motor neurons at 6 mo of age. We also report the formation of similar peripherin inclusions in presymptomatic transgenic mice expressing a mutant form of superoxide dismutase linked to ALS. Taken together, these results suggest that IF inclusions containing peripherin may play a contributory role in mot...

The Journal of Neuroscience : The Official Journal of the Society for Neuroscience

ABSTRACT

Acta Neuropathologica Communications

To test the hypothesis that the cerebrospinal fluid (CSF) could provide a spreading route for pat... more To test the hypothesis that the cerebrospinal fluid (CSF) could provide a spreading route for pathogenesis of amyotrophic lateral sclerosis (ALS), we have examined the effects of intraventricular infusion during 2 weeks of pooled CSF samples from sporadic ALS patients or control CSF samples into transgenic mice expressing human TDP43WT which do not develop pathological phenotypes. Infusion of ALS-CSF, but not of control CSF, triggered motor and cognitive dysfunction, as well as ALS-like pathological changes including TDP43 proteinopathy, neurofilament disorganization and neuroinflammation. In addition, the neuron-specific translational profiles from peptide analyses of immunoprecipitated ribosomes revealed dysregulation of multiple protein networks in response to ALS-CSF altering cytoskeletal organization, vesicle trafficking, mitochondrial function, and cell metabolism. With normal mice, similar ALS-CSF infusion induced mild motor dysfunction but without significant TDP43 pathology...

Neurotherapeutics

Withaferin-A, an active withanolide derived from the medicinal herbal plant Withania somnifera in... more Withaferin-A, an active withanolide derived from the medicinal herbal plant Withania somnifera induces autophagy, reduces TDP-43 proteinopathy, and improves cognitive function in transgenic mice expressing mutant TDP-43 modelling FTLD. TDP-43 is a nuclear DNA/RNA-binding protein with cellular functions in RNA transcription and splicing. Abnormal cytoplasmic aggregates of TDP-43 occur in several neurodegenerative diseases including amyotrophic lateral sclerosis (ALS), frontotemporal lobar degeneration (FTLD), and limbic-predominant age-related TDP-43 encephalopathy (LATE). To date, no effective treatment is available for TDP-43 proteinopathies. Here, we tested the effects of withaferin-A (WFA), an active withanolide extracted from the medicinal herbal plant Withania somnifera, in a transgenic mouse model of FTLD expressing a genomic fragment encoding mutant TDP-43G348C. WFA treatment ameliorated the cognitive performance of the TDP-43G348C mice, and it reduced NF-κB activity and neur...

Background: TDP-43 proteinopathy is a pathological hallmark of many neurodegenerative diseases in... more Background: TDP-43 proteinopathy is a pathological hallmark of many neurodegenerative diseases including amyotrophic lateral sclerosis (ALS) and frontotemporal dementia (FTD). So far, there is no therapy available for these neurodegenerative diseases. In addition, the impact of TDP-43 proteinopathy on neuronal translational profile remains unknown. Methods: Biochemical, immunohistology and assay-based studies were done with cell cultures and transgenic mice models. We also used a Ribotag approach combined with microarray and proteomic analyses to investigate the neuronal translational profiles in mouse model of ALS/FTD. Results: Here, we report that oral administration of a novel analog (IMS-088) of withaferin-A, an antagonist of nuclear factor kappa-B (NF-ĸB) essential modulator (NEMO), induces autophagy and reduced TDP-43 proteinopathy in the brain and spinal cord of transgenic mice expressing human TDP-43 mutants, models of ALS/FTD. Treatment with IMS-088 ameliorated cognitive im...

Molecular Neurobiology

Mutations in the gene encoding ubiquilin-2 (UBQLN2) are linked to amyotrophic lateral sclerosis (... more Mutations in the gene encoding ubiquilin-2 (UBQLN2) are linked to amyotrophic lateral sclerosis (ALS) and frontotemporal dementia (FTD). UBQLN2 plays a central role in ubiquitin proteasome system (UPS) and UBQLN2 up-regulation exacerbates TDP-43 cytoplasmic aggregates. To analyze interaction between UBQLN2 and TDP-43 and to produce a relevant ALS animal model, we have generated a new transgenic mouse expressing UBQLN2 P497H under the neurofilament heavy (NFH) gene promoter. The UBQLN2 P497H mice were then bred with our previously described TDP-43 G348C mice to generate double-transgenic UBQLN2 P497H ; TDP-43 G348C mice. With low-expression levels of UBQLN2, the double-transgenic mice developed TDP-43 cytosolic accumulations in motor neurons starting at 5 months of age. These double-transgenic mice exhibited motor neuron loss, muscle atrophy, as well as motor and cognitive deficits during aging. The microglia from double-transgenic mice were hyperresponsive to intraperitoneal injection of lipopolysaccharide (LPS). In vivo and in vitro analyses suggested that extra UBQLN2 proteins can exacerbate cytoplasmic TDP-43 accumulations by competing with the UPS for binding to ubiquitin. Thus, increasing the pool of ubiquitin promoted the UPS function with ensuing reduction of TDP-43 cytosolic accumulations. In conclusion, the double-transgenic UBQLN2 P497H ; TDP-43 G348C mice provides a unique mouse model of ALS/FTD with enhanced TDP-43 pathology that can be exploited for drug testing.

Scientific reports, Jan 21, 2018

Aggregation of mutant superoxide dismutase 1 (SOD1) is a pathological hallmark of a subset of fam... more Aggregation of mutant superoxide dismutase 1 (SOD1) is a pathological hallmark of a subset of familial ALS patients. However, the possible role of misfolded wild type SOD1 in human ALS is highly debated. To ascertain whether or not misfolded SOD1 is a common pathological feature in non-SOD1 ALS, we performed a blinded histological and biochemical analysis of post mortem brain and spinal cord tissues from 19 sporadic ALS, compared with a SOD1 A4V patient as well as Alzheimer's disease (AD) and non-neurological controls. Multiple conformation- or misfolded-specific antibodies for human SOD1 were compared. These were generated independently by different research groups and were compared using standardized conditions. Five different misSOD1 staining patterns were found consistently in tissue sections from SALS cases and the SOD1 A4V patient, but were essentially absent in AD and non-neurological controls. We have established clear experimental protocols and provide specific guidelin...

Translational psychiatry, Jan 24, 2018

Neurofilament (NFL) proteins have recently been found to play unique roles in synapses. NFL is kn... more Neurofilament (NFL) proteins have recently been found to play unique roles in synapses. NFL is known to interact with the GluN1 subunit of N-methyl-D-aspartic acid (NMDAR) and be reduced in schizophrenia though functional consequences are unknown. Here we investigated whether the interaction of NFL with GluN1 modulates synaptic transmission and schizophrenia-associated behaviors. The interaction of NFL with GluN1 was assessed by means of molecular, pharmacological, electrophysiological, magnetic resonance spectroscopy (MRS), and schizophrenia-associated behavior analyses. NFL deficits cause an NMDAR hypofunction phenotype including abnormal hippocampal function, as seen in schizophrenia. NFL-/- deletion in mice reduces dendritic spines and GluN1 protein levels, elevates ubiquitin-dependent turnover of GluN1 and hippocampal glutamate measured by MRS, and depresses hippocampal long-term potentiation. NMDAR-related behaviors are also impaired, including pup retrieval, spatial and socia...

Neurotherapeutics : the journal of the American Society for Experimental NeuroTherapeutics, 2018

Amyotrophic lateral sclerosis (ALS) is a fatal neurodegenerative disease which presently does not... more Amyotrophic lateral sclerosis (ALS) is a fatal neurodegenerative disease which presently does not have any efficient therapeutic approach. Pimozide, a Food and Drug Administration (FDA)-approved neuroepileptic drug, has been recently proposed as a promising treatment for ALS patients based on apparent stabilization of right hand muscles after a short-time administration. A new clinical trial started at the end of 2017 to recruit patients with a prolonged drug delivery schedule. Here, our aim was to investigate the effects of chronic administration of pimozide on disease progression and pathological events in two mouse models of ALS. Pimozide was administered every 2 days to transgenic mice bearing the ALS-linked A315T mutation on the human TAR DNA-binding protein 43 (TDP-43) gene and to mice carrying the human superoxide dismutase 1 (SOD1) gene with the ALS-linked G93A mutation. Chronic administration of pimozide exacerbated motor performances in both animal models and reduced survi...

Neuroreport, Jan 3, 2018

Amyotrophic lateral sclerosis (ALS) is a late-onset, fatal disorder in which motor neurons select... more Amyotrophic lateral sclerosis (ALS) is a late-onset, fatal disorder in which motor neurons selectively degenerate. Superoxide dismutase 1 (SOD1) was found to be a causative gene of familial ALS, and mutant SOD1 transgenic mice recapitulated ALS phenotypes. Analysis of these mice showed accumulation of misfolded SOD1 protein in motor neurons. Misfolded SOD1 accumulation was found in spinal motor neurons of both familial ALS patients with the SOD1 mutation and sporadic ALS patients. However, it is unclear what condition causes wild-type SOD1 misfolding in patients without the SOD1 mutation. Here, we generated induced pluripotent stem cells from mutant SOD1 transgenic mice, wild-type SOD1 transgenic mice, and control mice, and differentiated them into spinal motor neurons to analyze misfolded SOD1 accumulation. We found that misfolded SOD1 protein was accumulated in spinal motor neurons of both mutant and wild-type SOD1 transgenic mice as detected by a specific antibody against the mis...

JCI insight, Jan 16, 2017

Amyotrophic lateral sclerosis (ALS) is a rapidly progressing, fatal disorder with no effective tr... more Amyotrophic lateral sclerosis (ALS) is a rapidly progressing, fatal disorder with no effective treatment. We used simple genetic models of ALS to screen phenotypically for potential therapeutic compounds. We screened libraries of compounds in C. elegans, validated hits in zebrafish, and tested the most potent molecule in mice and in a small clinical trial. We identified a class of neuroleptics that restored motility in C. elegans and in zebrafish, and the most potent was pimozide, which blocked T-type Ca2+ channels in these simple models and stabilized neuromuscular transmission in zebrafish and enhanced it in mice. Finally, a short randomized controlled trial of sporadic ALS subjects demonstrated stabilization of motility and evidence of target engagement at the neuromuscular junction. Simple genetic models are, thus, useful in identifying promising compounds for the treatment of ALS, such as neuroleptics, which may stabilize neuromuscular transmission and prolong survival in this ...

Science translational medicine, May 24, 2017

Amyotrophic lateral sclerosis (ALS), a fatal disease causing progressive loss of motor neurons, s... more Amyotrophic lateral sclerosis (ALS), a fatal disease causing progressive loss of motor neurons, still has no effective treatment. We developed a phenotypic screen to repurpose existing drugs using ALS motor neuron survival as readout. Motor neurons were generated from induced pluripotent stem cells (iPSCs) derived from an ALS patient with a mutation in superoxide dismutase 1 (SOD1). Results of the screen showed that more than half of the hits targeted the Src/c-Abl signaling pathway. Src/c-Abl inhibitors increased survival of ALS iPSC-derived motor neurons in vitro. Knockdown of Src or c-Abl with small interfering RNAs (siRNAs) also rescued ALS motor neuron degeneration. One of the hits, bosutinib, boosted autophagy, reduced the amount of misfolded mutant SOD1 protein, and attenuated altered expression of mitochondrial genes. Bosutinib also increased survival in vitro of ALS iPSC-derived motor neurons from patients with sporadic ALS or other forms of familial ALS caused by mutations...

Human molecular genetics, Nov 30, 2016

Recent genetic studies yielded conflicting results regarding a role for the variant chromogranin ... more Recent genetic studies yielded conflicting results regarding a role for the variant chromogranin B (CHGB)(P413L) allele as a disease modifier in ALS. Moreover, potential deleterious effects of the CHGB(P413L) variant in ALS pathology have not been investigated. Here we report that in transfected cultured cells, the variant CHGB(L413) protein exhibited aberrant properties including mislocalization, failure to interact with mutant superoxide dismutase 1 (SOD1) and defective secretion. The CHGB(L413) transgene in SOD1(G37R) mice precipitated disease onset and pathological changes related to misfolded SOD1 specifically in female mice. However, the CHGB(L413) variant also slowed down disease progression in SOD1(G37R) mice, which is in line with a very slow disease progression that we report for a Swedish woman with ALS who is carrier of two mutant SOD1(D90A) alleles and two variant CHGB(P413L) and CHGB(R458Q) alleles. In contrast, overexpression of the common CHGB(P413) allele in SOD1(G3...

PLOS ONE, 2015

TAR DNA-binding protein 43 (TDP-43) is a major component in aggregates of ubiquitinated proteins ... more TAR DNA-binding protein 43 (TDP-43) is a major component in aggregates of ubiquitinated proteins in amyotrophic lateral sclerosis (ALS) and frontotemporal lobar degeneration (FTLD). Here we report that lipopolysaccharide (LPS)-induced inflammation can promote TDP-43 mislocalization and aggregation. In culture, microglia and astrocytes exhibited TDP-43 mislocalization after exposure to LPS. Likewise, treatment of the motoneuron-like NSC-34 cells with TNF-alpha (TNF-α) increased the cytoplasmic levels of TDP-43. In addition, the chronic intraperitoneal injection of LPS at a dose of 1mg/kg in TDP-43 A315T transgenic mice exacerbated the pathological TDP-43 accumulation in the cytoplasm of spinal motor neurons and it enhanced the levels of TDP-43 aggregation. These results suggest that inflammation may contribute to development or exacerbation of TDP-43 proteinopathies in neurodegenerative disorders.

Handbook of Clinical Neurophysiology, 2004

... JP. JULIEN AND J. KRIZ Dubois M, Strazielle C, Julien JP, Lalonde R (2005a). Mice with the de... more ... JP. JULIEN AND J. KRIZ Dubois M, Strazielle C, Julien JP, Lalonde R (2005a). Mice with the deleted neurofilament of low molecular weight (Nefl) gene: 2. Effects on motor functions and spatial orientation. ... Dubois M, Lalonde R, Julien JP, Strazielle C (2005b). ...

Advances in Neurobiology, 2010

... Rodolphe Perrot and Jean-Pierre Julien ... 269 J.-P. Julien (B) Department of Anatomy and Phy... more ... Rodolphe Perrot and Jean-Pierre Julien ... 269 J.-P. Julien (B) Department of Anatomy and Physiology, Centre de Recherche du Centre Hospitalier, Universitaire de Québec, Laval University, Sainte-Foy, QC, Canada G1V 4G2 e-mail: jean-pierre.julien@crchul.ulaval.ca 261 ...

Nature Communications, 2015

The dynamic adjustment of hearing sensitivity and frequency selectivity is mediated by the medial... more The dynamic adjustment of hearing sensitivity and frequency selectivity is mediated by the medial olivocochlear efferent reflex, which suppresses the gain of the 'cochlear amplifier' in each ear. Such efferent feedback is important for promoting discrimination of sounds in background noise, sound localization and protecting the cochleae from acoustic overstimulation. However, the sensory driver for the olivocochlear reflex is unknown. Here, we resolve this longstanding question using a mouse model null for the gene encoding the type III intermediate filament peripherin (Prph). Prph (À / À) mice lacked type II spiral ganglion neuron innervation of the outer hair cells, whereas innervation of the inner hair cells by type I spiral ganglion neurons was normal. Compared with Prph (þ / þ) controls, both contralateral and ipsilateral olivocochlear efferent-mediated suppression of the cochlear amplifier were absent in Prph (À / À) mice, demonstrating that outer hair cells and their type II afferents constitute the sensory drive for the olivocochlear efferent reflex.