@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{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{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{pmid33021970,

title = {Monoclonal full-length antibody against TAR DNA binding protein 43 reduces related proteinopathy in neurons},

author = {Silvia Pozzi and Philippe Codron and Geneviève Soucy and Laurence Renaud and Pierre Junior Cordeau and Kallol Dutta and Christine Bareil and Jean-Pierre Julien},

doi = {10.1172/jci.insight.140420},

issn = {2379-3708},

year  = {2020},

date = {2020-11-01},

journal = {JCI Insight},

volume = {5},

number = {21},

abstract = {Amyotrophic lateral sclerosis (ALS) and frontotemporal lobar degeneration (FTLD), 2 incurable neurodegenerative disorders, share the same pathological hallmark named TDP43 (TAR DNA binding protein 43) proteinopathy. This event is characterized by a consistent cytoplasmic mislocalization and aggregation of the protein TDP43, which loses its physiological properties, leading neurons to death. Antibody-based approaches are now emerging interventions in the field of neurodegenerative disorders. Here, we tested the target specificity, in vivo distribution, and therapeutic efficacy of a monoclonal full-length antibody, named E6, in TDP43-related conditions. We observed that the antibody recognizes specifically the cytoplasmic fraction of TDP43. We demonstrated its ability in targeting large neurons in the spinal cord of mice and in reducing TDP43 mislocalization and NF-κB activation. We also recognized the proteasome as well as the lysosome machineries as possible mechanisms used by the antibody to reduce TDP43 proteinopathy. To our knowledge, this is the first report showing the therapeutic efficacy and feasibility of a full-length antibody against TDP43 in reducing TDP43 proteinopathy in spinal neurons of an ALS/FTLD mouse model.},

keywords = {},

pubstate = {published},

tppubtype = {article}

}

@article{pmid30667370,

title = {Virus-mediated delivery of antibody targeting TAR DNA-binding protein-43 mitigates associated neuropathology},

author = {Silvia Pozzi and Sai Sampath Thammisetty and Philippe Codron and Reza Rahimian and Karine Valérie Plourde and Geneviève Soucy and Christine Bareil and Daniel Phaneuf and Jasna Kriz and Claude Gravel and Jean-Pierre Julien},

doi = {10.1172/JCI123931},

issn = {1558-8238},

year  = {2019},

date = {2019-02-01},

journal = {J Clin Invest},

volume = {129},

number = {4},

pages = {1581--1595},

abstract = {The cytoplasmic aggregation of TAR DNA-binding protein-43 (TDP-43) is a hallmark of degenerating neurons in amyotrophic lateral sclerosis (ALS) and subsets of frontotemporal dementia (FTD). In order to reduce TDP-43 pathology, we generated single-chain (scFv) antibodies against the RNA recognition motif 1 (RRM1) of TDP-43, which is involved in abnormal protein self-aggregation and interaction with p65 NF-κB. Virus-mediated delivery into the nervous system of a scFv antibody, named VH7Vk9, reduced microgliosis in a mouse model of acute neuroinflammation and mitigated cognitive impairment, motor defects, TDP-43 proteinopathy, and neuroinflammation in transgenic mice expressing ALS-linked TDP-43 mutations. These results suggest that antibodies targeting the RRM1 domain of TDP-43 might provide new therapeutic avenues for the treatment of ALS and FTD.},

keywords = {},

pubstate = {published},

tppubtype = {article}

}

@article{pmid29790082,

title = {Chronic Administration of Pimozide Fails to Attenuate Motor and Pathological Deficits in Two Mouse Models of Amyotrophic Lateral Sclerosis},

author = {Silvia Pozzi and Sai Sampath Thammisetty and Jean-Pierre Julien},

doi = {10.1007/s13311-018-0634-3},

issn = {1878-7479},

year  = {2018},

date = {2018-07-01},

journal = {Neurotherapeutics},

volume = {15},

number = {3},

pages = {715--727},

abstract = {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 survival in SOD1 mice. In TDP-43T, it decreased the percentage of innervated neuromuscular junctions (NMJs) and increased the accumulation of insoluble TDP-43. In SOD1 mice, pimozide had no effects on NMJ innervation or motoneuron loss, but it increased the levels of misfolded SOD1. We conclude that a chronic administration of pimozide did not confer beneficial effects on disease progression in two mouse models of ALS. In light of a new clinical trial on ALS patients with a chronic regime of pimozide, these results with mouse models suggest prudence and careful monitoring of ALS patients subjected to pimozide treatment.},

keywords = {},

pubstate = {published},

tppubtype = {article}

}