@article{pmid40940222,

title = {Antibody targeting TDP-43 mitigates pathogenic pathways induced by the cerebrospinal fluid of ALS},

author = {Amélie Poulin-Brière and Silvia Pozzi and Jean-Pierre Julien},

doi = {10.1016/j.neurot.2025.e00737},

issn = {1878-7479},

year  = {2025},

date = {2025-09-01},

journal = {Neurotherapeutics},

pages = {e00737},

abstract = {Amyotrophic lateral sclerosis (ALS) is an incurable neurodegenerative disease characterized by the cytoplasmic mislocalization and accumulation of TAR DNA binding protein 43 (TDP-43). We reported previously the protective effects in a transgenic mouse model expressing ALS-linked mutant TDP-43 of a monoclonal antibody, called E6, binding specifically to the RNA Recognition Motif 1 (RRM1) domain of TDP-43. Here, we tested the effects of E6 antibody in an animal model of sporadic ALS based on the intracerebroventricular (i.c.v.) infusion during 14 days of cerebrospinal fluid (CSF) from sporadic ALS patients into transgenic mice expressing human TDP-43. Either intrathecal (i.t.) or i.c.v. injection of E6 antibody conferred protective effects in this model of disease. Thus, the CSF-inoculated E6 antibody reduced motor and cognitive impairments, mitigated TDP-43 proteinopathy and prevented neurofilament (Nf) disorganization in cortical and spinal neurons. Administration of E6 antibody reduced the loss of motor neurons in the spinal cord and the denervation of neuromuscular junctions. Moreover, E6 antibody promoted a switch toward features associated with a protective phenotype of microglial activation characterized by enhanced phagocytic function and reduced secretion of pro-inflammatory cytokines. The results suggest that an immunotherapy targeting the RRM1 domain of TDP-43 may confer protection against pathogenic pathways triggered by the CSF of ALS patients.},

keywords = {},

pubstate = {published},

tppubtype = {article}

}

@article{pmid39778789,

title = {Virus-mediated delivery of single-chain antibody targeting TDP-43 protects against neuropathology, cognitive impairment and motor deficit caused by chronic cerebral hypoperfusion},

author = {Anna Ania Chami and Claude Gravel and Yuan Cheng Weng and Jasna Kriz and Jean-Pierre Julien},

doi = {10.1016/j.expneurol.2025.115138},

issn = {1090-2430},

year  = {2025},

date = {2025-03-01},

journal = {Exp Neurol},

volume = {385},

pages = {115138},

abstract = {Chronic cerebral hypoperfusion induced by permanent unilateral common carotid artery occlusion in mice was recently found to induce an age-dependent formation of insoluble cytoplasmic TDP-43 aggregates reminiscent of pathological changes found in human vascular dementia. In this model, the gradual deregulation of TDP-43 homeostasis in cortical neurons was associated with marked cognitive and motor deficits. To target the TDP-43-mediated toxicity in this model, we generated an adeno-associated virus vector encoding a single-chain antibody against TDP-43, called scFv-E6, designed for pan-neuronal transduction following intravenous administration. Injected prior to brain hypoperfusion, this tonic virus-mediated delivery of the scFv-E6 antibody reduced formation of cytoplasmic TDP-43 aggregates in cortical neurons, boosted levels of autophagy markers and attenuated microgliosis. Moreover, the novel object recognition and grip strength tests revealed that neuronal expression of scFv-E6 prevented the cognitive impairment and loss of motor performance caused by two-months of cerebral hypoperfusion. The robust protective effects of scFv-E6 antibody in this model suggest a key role of TDP-43 in neuronal damage and symptom phenotypes caused by chronic cerebral hypoperfusion. Accordingly, TDP-43 should be considered as a new therapeutic target in drug development, including antibody approaches, for treatment of vascular dementia.},

keywords = {},

pubstate = {published},

tppubtype = {article}

}

@article{pmid38522514,

title = {Tryptophan residues in TDP-43 and SOD1 modulate the cross-seeding and toxicity of SOD1},

author = {Edward Pokrishevsky and Michéle G DuVal and Luke McAlary and Sarah Louadi and Silvia Pozzi and Andrei Roman and Steven S Plotkin and Anke Dijkstra and Jean-Pierre Julien and W Ted Allison and Neil R Cashman},

doi = {10.1016/j.jbc.2024.107207},

issn = {1083-351X},

year  = {2024},

date = {2024-05-01},

journal = {J Biol Chem},

volume = {300},

number = {5},

pages = {107207},

abstract = {Amyotrophic lateral sclerosis (ALS) is a fatal neurodegenerative disease of motor neurons. Neuronal superoxide dismutase-1 (SOD1) inclusion bodies are characteristic of familial ALS with SOD1 mutations, while a hallmark of sporadic ALS is inclusions containing aggregated WT TAR DNA-binding protein 43 (TDP-43). We show here that co-expression of mutant or WT TDP-43 with SOD1 leads to misfolding of endogenous SOD1 and aggregation of SOD1 reporter protein SOD1-GFP in human cell cultures and promotes synergistic axonopathy in zebrafish. Intriguingly, this pathological interaction is modulated by natively solvent-exposed tryptophans in SOD1 (tryptophan-32) and TDP-43 RNA-recognition motif RRM1 (tryptophan-172), in concert with natively sequestered TDP-43 N-terminal domain tryptophan-68. TDP-43 RRM1 intrabodies reduce WT SOD1 misfolding in human cell cultures, via blocking tryptophan-172. Tryptophan-68 becomes antibody-accessible in aggregated TDP-43 in sporadic ALS motor neurons and cell culture. 5-fluorouridine inhibits TDP-43-induced G85R-GFP SOD1 aggregation in human cell cultures and ameliorates axonopathy in zebrafish, via its interaction with SOD1 tryptophan-32. Collectively, our results establish a novel and potentially druggable tryptophan-mediated mechanism whereby two principal ALS disease effector proteins might directly interact in disease.},

keywords = {},

pubstate = {published},

tppubtype = {article}

}

@article{pmid38790979,

title = {Inhibition of NF-κB with an Analog of Withaferin-A Restores TDP-43 Homeostasis and Proteome Profiles in a Model of Sporadic ALS},

author = {Pooja Shree Mishra and Daniel Phaneuf and Hejer Boutej and Vincent Picher-Martel and Nicolas Dupre and Jasna Kriz and Jean-Pierre Julien},

doi = {10.3390/biomedicines12051017},

issn = {2227-9059},

year  = {2024},

date = {2024-05-01},

journal = {Biomedicines},

volume = {12},

number = {5},

abstract = {The current knowledge on pathogenic mechanisms in amyotrophic lateral sclerosis (ALS) has widely been derived from studies with cell and animal models bearing ALS-linked genetic mutations. However, it remains unclear to what extent these disease models are of relevance to sporadic ALS. Few years ago, we reported that the cerebrospinal fluid (CSF) from sporadic ALS patients contains toxic factors for disease transmission in mice via chronic intracerebroventricular (i.c.v.) infusion. Thus a 14-day i.c.v. infusion of pooled CSF samples from ALS cases in mice provoked motor impairment as well as ALS-like pathological features. This offers a unique paradigm to test therapeutics in the context of sporadic ALS disease. Here, we tested a new Withaferin-A analog (IMS-088) inhibitor of NF-κB that was found recently to mitigate disease phenotypes in mouse models of familial disease expressing TDP-43 mutant. Our results show that oral intake of IMS-088 ameliorated motor performance of mice infused with ALS-CSF and it alleviated pathological changes including TDP-43 proteinopathy, neurofilament disorganization, and neuroinflammation. Moreover, CSF infusion experiments were carried out with transgenic mice having neuronal expression of tagged ribosomal protein (hNfL-RFP mice), which allowed immunoprecipitation of neuronal ribosomes for analysis by mass spectrometry of the translational peptide signatures. The results indicate that treatment with IMS-088 prevented many proteomic alterations associated with exposure to ALS-CSF involving pathways related to cytoskeletal changes, inflammation, metabolic dysfunction, mitochondria, UPS, and autophagy dysfunction. The effective disease-modifying effects of this drug in a mouse model based on i.c.v. infusion of ALS-CSF suggest that the NF-κB signaling pathway represents a compelling therapeutic target for sporadic ALS.},

keywords = {},

pubstate = {published},

tppubtype = {article}

}

@article{pmid37974279,

title = {Neuronal dysfunction caused by FUSR521G promotes ALS-associated phenotypes that are attenuated by NF-κB inhibition},

author = {Mari Carmen Pelaez and Antoine Desmeules and Pauline A Gelon and Bastien Glasson and Laetitia Marcadet and Alicia Rodgers and Daniel Phaneuf and Silvia Pozzi and Paul A Dutchak and Jean-Pierre Julien and Chantelle F Sephton},

doi = {10.1186/s40478-023-01671-1},

issn = {2051-5960},

year  = {2023},

date = {2023-11-01},

journal = {Acta Neuropathol Commun},

volume = {11},

number = {1},

pages = {182},

abstract = {Amyotrophic lateral sclerosis (ALS) and frontotemporal dementia (FTD) are related neurodegenerative diseases that belong to a common disease spectrum based on overlapping clinical, pathological and genetic evidence. Early pathological changes to the morphology and synapses of affected neuron populations in ALS/FTD suggest a common underlying mechanism of disease that requires further investigation. Fused in sarcoma (FUS) is a DNA/RNA-binding protein with known genetic and pathological links to ALS/FTD. Expression of ALS-linked FUS mutants in mice causes cognitive and motor defects, which correlate with loss of motor neuron dendritic branching and synapses, in addition to other pathological features of ALS/FTD. The role of ALS-linked FUS mutants in causing ALS/FTD-associated disease phenotypes is well established, but there are significant gaps in our understanding of the cell-autonomous role of FUS in promoting structural changes to motor neurons, and how these changes relate to disease progression. Here we generated a neuron-specific FUS-transgenic mouse model expressing the ALS-linked human FUSR521G variant, hFUS, to investigate the cell-autonomous role of FUSR521G in causing loss of dendritic branching and synapses of motor neurons, and to understand how these changes relate to ALS-associated phenotypes. Longitudinal analysis of mice revealed that cognitive impairments in juvenile hFUS mice coincide with reduced dendritic branching of cortical motor neurons in the absence of motor impairments or changes in the neuromorphology of spinal motor neurons. Motor impairments and dendritic attrition of spinal motor neurons developed later in aged hFUS mice, along with FUS cytoplasmic mislocalisation, mitochondrial abnormalities and glial activation. Neuroinflammation promotes neuronal dysfunction and drives disease progression in ALS/FTD. The therapeutic effects of inhibiting the pro-inflammatory nuclear factor kappa B (NF-κB) pathway with an analog of Withaferin A, IMS-088, were assessed in symptomatic hFUS mice and were found to improve cognitive and motor function, increase dendritic branches and synapses of motor neurons, and attenuate other ALS/FTD-associated pathological features. Treatment of primary cortical neurons expressing FUSR521G with IMS-088 promoted the restoration of dendritic mitochondrial numbers and mitochondrial activity to wild-type levels, suggesting that inhibition of NF-κB permits the restoration of mitochondrial stasis in our models. Collectively, this work demonstrates that FUSR521G has a cell-autonomous role in causing early pathological changes to dendritic and synaptic structures of motor neurons, and that these changes precede motor defects and other well-known pathological features of ALS/FTD. Finally, these findings provide further support that modulation of the NF-κB pathway in ALS/FTD is an important therapeutic approach to attenuate disease.},

keywords = {},

pubstate = {published},

tppubtype = {article}

}

@article{pmid37410912,

title = {Transactive response DNA-binding protein 43 is enriched at the centrosome in human cells},

author = {Alexia Bodin and Logan Greibill and Julien Gouju and Franck Letournel and Silvia Pozzi and Jean-Pierre Julien and Laurence Renaud and Delphine Bohl and Stéphanie Millecamps and Christophe Verny and Julien Cassereau and Guy Lenaers and Arnaud Chevrollier and Anne-Marie Tassin and Philippe Codron},

doi = {10.1093/brain/awad228},

issn = {1460-2156},

year  = {2023},

date = {2023-09-01},

journal = {Brain},

volume = {146},

number = {9},

pages = {3624--3633},

abstract = {The centrosome, as the main microtubule organizing centre, plays key roles in cell polarity, genome stability and ciliogenesis. The recent identification of ribosomes, RNA-binding proteins and transcripts at the centrosome suggests local protein synthesis. In this context, we hypothesized that TDP-43, a highly conserved RNA binding protein involved in the pathophysiology of amyotrophic lateral sclerosis and frontotemporal lobar degeneration, could be enriched at this organelle. Using dedicated high magnification sub-diffraction microscopy on human cells, we discovered a novel localization of TDP-43 at the centrosome during all phases of the cell cycle. These results were confirmed on purified centrosomes by western blot and immunofluorescence microscopy. In addition, the co-localization of TDP-43 and pericentrin suggested a pericentriolar enrichment of the protein, leading us to hypothesize that TDP-43 might interact with local mRNAs and proteins. Supporting this hypothesis, we found four conserved centrosomal mRNAs and 16 centrosomal proteins identified as direct TDP-43 interactors. More strikingly, all the 16 proteins are implicated in the pathophysiology of TDP-43 proteinopathies, suggesting that TDP-43 dysfunction in this organelle contributes to neurodegeneration. This first description of TDP-43 centrosomal enrichment paves the way for a more comprehensive understanding of TDP-43 physiology and pathology.},

keywords = {},

pubstate = {published},

tppubtype = {article}

}

@article{pmid37650499,

title = {Ultrasensitive digital immunoassays for SOD1 conformation in amyotrophic lateral sclerosis},

author = {Lisa Morichon and Christophe Hirtz and Laurent Tiers and Alexandre Mezghrani and Cédric Raoul and Florence Esselin and Elisa De La Cruz and Jean-Pierre Julien and William Camu and Sylvain Lehmann},

doi = {10.4155/bio-2023-0103},

issn = {1757-6199},

year  = {2023},

date = {2023-08-01},

journal = {Bioanalysis},

volume = {15},

number = {15},

pages = {927--936},

abstract = { The aim of this study was to detect misfolded Cu/Zn SOD1 as a potential biomarker for amyotrophic lateral sclerosis (ALS).  Two ultrasensitive immunodetection assays were developed for the quantification of total and misfolded SOD1.  The detection of total and misfolded SOD1 was possible in human serum and cerebrospinal fluid. Total SOD1 was increased in cerebrospinal fluid from ALS patients. Misfolded SOD1 had low and variable expression in both control and ALS patient samples.  These assays hold promise for improving our understanding of ALS and its detection, and could lead to more effective treatment options in the future. Further studies in larger cohorts are now required.},

keywords = {},

pubstate = {published},

tppubtype = {article}

}

@article{pmid37268847,

title = {Axonal Transport Defect in Gigaxonin Deficiency Rescued by Tubastatin A},

author = {Banshi Nath and Daniel Phaneuf and Jean-Pierre Julien},

doi = {10.1007/s13311-023-01393-1},

issn = {1878-7479},

year  = {2023},

date = {2023-07-01},

journal = {Neurotherapeutics},

volume = {20},

number = {4},

pages = {1215--1228},

abstract = {Giant axonal neuropathy (GAN) is a disease caused by a deficiency of gigaxonin, a mediator of the degradation of intermediate filament (IF) proteins. A lack of gigaxonin alters the turnover of IF proteins, provoking accumulation and disorganization of neurofilaments (NFs) in neurons, a hallmark of the disease. However, the effects of IF disorganization on neuronal function remain unknown. Here, we report that cultured embryonic dorsal root ganglia (DRG) neurons derived from Gan mice exhibit accumulations of IF proteins and defects in fast axonal transport of organelles. Kymographs generated by time-lapse microscopy revealed substantial reduction of anterograde movements of mitochondria and lysosomes in axons of Gan DRG neurons. Treatment of Gan DRG neurons with Tubastatin A (TubA) increased the levels of acetylated tubulin and it restored the normal axonal transport of these organelles. Furthermore, we tested the effects of TubA in a new mouse model of GAN consisting of Gan mice with overexpression of peripherin (Prph) transgene. Treatment of 12-month-old Gan;TgPer mice with TubA led to a slight amelioration of motor function, especially a significant improvement of gait performance as measured by footprint analyses. Moreover, TubA treatment reduced the abnormal accumulations of Prph and NF proteins in spinal neurons and it boosted the levels of Prph transported into peripheral nerve axons. These results suggest that drug inhibitors of histone deacetylase aiming to enhance axonal transport should be considered as a potential treatment for GAN disease.},

keywords = {},

pubstate = {published},

tppubtype = {article}

}

@article{pmid37371694,

title = {Emerging Trends in the Field of Inflammation and Proteinopathy in ALS/FTD Spectrum Disorder},

author = {Fabiola De Marchi and Toni Franjkic and Paride Schito and Tommaso Russo and Jerneja Nimac and Anna A Chami and Angelica Mele and Lea Vidatic and Jasna Kriz and Jean-Pierre Julien and Gordana Apic and Robert B Russell and Boris Rogelj and Jason R Cannon and Marco Baralle and Federica Agosta and Silva Hecimovic and Letizia Mazzini and Emanuele Buratti and Ivana Munitic},

doi = {10.3390/biomedicines11061599},

issn = {2227-9059},

year  = {2023},

date = {2023-05-01},

journal = {Biomedicines},

volume = {11},

number = {6},

abstract = {Proteinopathy and neuroinflammation are two main hallmarks of neurodegenerative diseases. They also represent rare common events in an exceptionally broad landscape of genetic, environmental, neuropathologic, and clinical heterogeneity present in patients. Here, we aim to recount the emerging trends in amyotrophic lateral sclerosis (ALS) and frontotemporal degeneration (FTD) spectrum disorder. Our review will predominantly focus on neuroinflammation and systemic immune imbalance in ALS and FTD, which have recently been highlighted as novel therapeutic targets. A common mechanism of most ALS and ~50% of FTD patients is dysregulation of TAR DNA-binding protein 43 (TDP-43), an RNA/DNA-binding protein, which becomes depleted from the nucleus and forms cytoplasmic aggregates in neurons and glia. This, in turn, via both gain and loss of function events, alters a variety of TDP-43-mediated cellular events. Experimental attempts to target TDP-43 aggregates or manipulate crosstalk in the context of inflammation will be discussed. Targeting inflammation, and the immune system in general, is of particular interest because of the high plasticity of immune cells compared to neurons.},

keywords = {},

pubstate = {published},

tppubtype = {article}

}

@article{pmid37137704,

title = {A New Mouse Model of Giant Axonal Neuropathy with Overt Phenotypes and Neurodegeneration Driven by Neurofilament Disorganization},

author = {Banshi Nath and Jean-Pierre Julien},

doi = {10.1523/JNEUROSCI.1959-22.2023},

issn = {1529-2401},

year  = {2023},

date = {2023-05-01},

journal = {J Neurosci},

volume = {43},

number = {22},

pages = {4174--4189},

abstract = {Research on pathogenic mechanisms underlying giant axonal neuropathy (GAN), a disease caused by a deficiency of gigaxonin, has been hindered by the lack of appropriate animal models exhibiting substantial symptoms and large neurofilament (NF) swellings, a hallmark of the human disease. It is well established that intermediate filament (IF) proteins are substrates for gigaxonin-mediated degradation. However, it has remained unknown to what extent NF accumulations contribute to GAN pathogenesis. Here, we report the generation of a new mouse model of GAN that is based on crossing transgenic mice overexpressing peripherin (Prph) with mice knockout for  The Gan;TgPer mice developed early onset sensory-motor deficits along with IF accumulations made up of NF proteins and of Prph, causing swelling of spinal neurons at a young age. Abundant inclusion bodies composed of disorganized IFs were also detected in the brain of Gan;TgPer mice. At 12 months of age, the Gan;TgPer mice exhibited cognitive deficits as well as severe sensory and motor defects. The disease was associated with neuroinflammation and substantial loss of cortical neurons and spinal neurons. Giant axons (≥160 μm) enlarged by disorganized IFs, a hallmark of GAN disease, were also detected in dorsal and ventral roots of the Gan;TgPer mice. These results, obtained with both sexes, support the view that the disorganization of IFs can drive some neurodegenerative changes caused by gigaxonin deficiency. This new mouse model should be useful to investigate the pathogenic changes associated with GAN disease and for drug testing. Research on pathogenic mechanism and treatment of GAN has been hampered by the lack of animal models exhibiting overt phenotypes and substantial neurofilament disorganization, a hallmark of the disease. Moreover, it remains unknown whether neurologic defects associated with gigaxonin deficiency in GAN are because of neurofilament disorganization as gigaxonin may also act on other protein substrates to mediate their degradation. This study reports the generation of a new mouse model of GAN based on overexpression of Prph in the context of targeted disruption of gigaxonin gene. The results support the view that neurofilament disorganization may contribute to neurodegenerative changes in GAN disease. The Gan;TgPer mice provide a unique animal model of GAN for drug testing.},

keywords = {},

pubstate = {published},

tppubtype = {article}

}