@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{pmid36973269,

title = {The small GTPase Rit2 modulates LRRK2 kinase activity, is required for lysosomal function and protects against alpha-synuclein neuropathology},

author = {Julia Obergasteiger and Anne-Marie Castonguay and Sara Pizzi and Stefano Magnabosco and Giulia Frapporti and Evy Lobbestael and Veerle Baekelandt and Andrew A Hicks and Peter P Pramstaller and Claude Gravel and Corrado Corti and Martin Lévesque and Mattia Volta},

doi = {10.1038/s41531-023-00484-2},

issn = {2373-8057},

year  = {2023},

date = {2023-03-01},

journal = {NPJ Parkinsons Dis},

volume = {9},

number = {1},

pages = {44},

abstract = {In Parkinson's disease (PD) misfolded alpha-synuclein (aSyn) accumulates in the substantia nigra, where dopaminergic neurons are progressively lost. The mechanisms underlying aSyn pathology are still unclear, but they are hypothesized to involve the autophagy-lysosome pathway (ALP). LRRK2 mutations are a major cause of familial and sporadic PD, and LRRK2 kinase activity has been shown to be involved in pS129-aSyn inclusion modulation. We observed selective downregulation of the novel PD risk factor RIT2 in vitro and in vivo. Rit2 overexpression in G2019S-LRRK2 cells rescued ALP abnormalities and diminished aSyn inclusions. In vivo, viral mediated overexpression of Rit2 operated neuroprotection against AAV-A53T-aSyn. Furthermore, Rit2 overexpression prevented the A53T-aSyn-dependent increase of LRRK2 kinase activity in vivo. On the other hand, reduction of Rit2 levels leads to defects in the ALP, similar to those induced by the G2019S-LRRK2 mutation. Our data indicate that Rit2 is required for correct lysosome function, inhibits overactive LRRK2 to ameliorate ALP impairment, and counteracts aSyn aggregation and related deficits. Targeting Rit2 could represent an effective strategy to combat neuropathology in familial and idiopathic PD.},

keywords = {},

pubstate = {published},

tppubtype = {article}

}

@article{pmid33104039,

title = {Treating Parkinson's Disease with Antibodies: Previous Studies and Future Directions},

author = {Anne-Marie Castonguay and Claude Gravel and Martin Lévesque},

doi = {10.3233/JPD-202221},

issn = {1877-718X},

year  = {2021},

date = {2021-01-01},

journal = {J Parkinsons Dis},

volume = {11},

number = {1},

pages = {71--92},

abstract = {Parkinson's disease is a neurodegenerative disorder mainly characterized by the degeneration of dopaminergic neurons in the substantia nigra. Degenerating neurons contain abnormal aggregates called Lewy bodies, that are predominantly composed of the misfolded and/or mutated alpha-synuclein protein. Post-translational modifications, cellular stress, inflammation and gene mutations are thought to trigger its pathological misfolding and aggregation. With alpha-synuclein pathology being strongly associated with dopaminergic neuronal toxicity, strategies aimed to reduce its burden are expected to be beneficial in slowing disease progression. Moreover, multiple sources of evidence suggest a cell-to-cell transmission of pathological alpha-synuclein in a prion-like manner. Therefore, antibodies targeting extra- or intracellular alpha-synuclein could be efficient in limiting the aggregation and transmission. Several active and passive immunization strategies have been explored to target alpha-synuclein. Here, we summarize immunotherapeutic approaches that were tested in pre-clinical or clinical studies in the last two decades in an attempt to treat Parkinson's disease.},

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{pmid26791230,

title = {IL-10 Controls Early Microglial Phenotypes and Disease Onset in ALS Caused by Misfolded Superoxide Dismutase 1},

author = {Mathieu Gravel and Louis-Charles Béland and Geneviève Soucy and Essam Abdelhamid and Reza Rahimian and Claude Gravel and Jasna Kriz},

doi = {10.1523/JNEUROSCI.0854-15.2016},

issn = {1529-2401},

year  = {2016},

date = {2016-01-01},

journal = {J Neurosci},

volume = {36},

number = {3},

pages = {1031--1048},

abstract = {While reactive microgliosis is a hallmark of advanced stages of amyotrophic lateral sclerosis (ALS), the role of microglial cells in events initiating and/or precipitating disease onset is largely unknown. Here we provide novel in vivo evidence of a distinct adaptive shift in functional microglial phenotypes in preclinical stages of superoxide dismutase 1 (SOD1)-mutant-mediated disease. Using a mouse model for live imaging of microglial activation crossed with SOD1(G93A) and SOD1(G37R) mouse models, we discovered that the preonset phase of SOD1-mediated disease is characterized by development of distinct anti-inflammatory profile and attenuated innate immune/TLR2 responses to lipopolysaccharide (LPS) challenge. This microglial phenotype was associated with a 16-fold overexpression of anti-inflammatory cytokine IL-10 in baseline conditions followed by a 4.5-fold increase following LPS challenge. While infusion of IL-10R blocking antibody, initiated at day 60, caused a significant increase in markers of microglial activation and precipitated clinical onset of disease, a targeted overexpression of IL-10 in microglial cells, delivered via viral vectors expressed under CD11b promoter, significantly delayed disease onset and increased survival of SOD1(G93A) mice. We propose that the high IL-10 levels in resident microglia in early ALS represent a homeostatic and compensatory "adaptive immune escape" mechanism acting as a nonneuronal determinant of clinical onset of disease. Significance statement: We report here for the first time that changing the immune profile of brain microglia may significantly affect clinical onset and duration of disease in ALS models. We discovered that in presymptomatic disease microglial cells overexpress anti-inflammatory cytokine IL-10. Given that IL-10 is major homeostatic cytokine and its production becomes deregulated with aging, this may suggest that the capacity of microglia to adequately produce IL-10 may be compromised in ALS. We show that blocking IL-10 increased inflammation and precipitated clinical disease onset, whereas overexpression of IL-10 in microglia using a gene therapy approach significantly delayed disease onset and increased survival of ALS mice. Based on our results, we propose that targeted overexpression of IL-10 in microglia may have therapeutic potential in ALS.},

keywords = {},

pubstate = {published},

tppubtype = {article}

}

@article{pmid24394188,

title = {Adeno-associated virus-mediated delivery of a recombinant single-chain antibody against misfolded superoxide dismutase for treatment of amyotrophic lateral sclerosis},

author = {Priyanka Patel and Jasna Kriz and Mathieu Gravel and Geneviève Soucy and Christine Bareil and Claude Gravel and Jean-Pierre Julien},

doi = {10.1038/mt.2013.239},

issn = {1525-0024},

year  = {2014},

date = {2014-03-01},

journal = {Mol Ther},

volume = {22},

number = {3},

pages = {498--510},

abstract = {There is emerging evidence that the misfolding of superoxide dismutase 1 (SOD1) may represent a common pathogenic event in both familial and sporadic amyotrophic lateral sclerosis (ALS). To reduce the burden of misfolded SOD1 species in the nervous system, we have tested a novel therapeutic approach based on adeno-associated virus (AAV)-mediated tonic expression of a DNA construct encoding a secretable single-chain fragment variable (scFv) antibody composed of the variable heavy and light chain regions of a monoclonal antibody (D3H5) binding specifically to misfolded SOD1. A single intrathecal injection of the AAV encoding the single-chain antibody in SOD1(G93A) mice at 45 days of age resulted in sustained expression of single-chain antibodies in the spinal cord, and it delayed disease onset and extension of life span by up to 28%, in direct correlation with scFv titers in the spinal cord. The treatment caused attenuation of neuronal stress signals and reduction in levels of misfolded SOD1 in the spinal cord of SOD1(G93A) mice. From these results, we propose that an immunotherapy based on intrathecal inoculation of AAV encoding a secretable scFv against misfolded SOD1 should be considered as potential treatment for ALS, especially for individuals carrying SOD1 mutations.},

keywords = {},

pubstate = {published},

tppubtype = {article}

}

@article{pmid16355225,

title = {BDNF from microglia causes the shift in neuronal anion gradient underlying neuropathic pain},

author = {Jeffrey A M Coull and Simon Beggs and Dominic Boudreau and Dominick Boivin and Makoto Tsuda and Kazuhide Inoue and Claude Gravel and Michael W Salter and Yves De Koninck},

doi = {10.1038/nature04223},

issn = {1476-4687},

year  = {2005},

date = {2005-12-01},

journal = {Nature},

volume = {438},

number = {7070},

pages = {1017--1021},

abstract = {Neuropathic pain that occurs after peripheral nerve injury depends on the hyperexcitability of neurons in the dorsal horn of the spinal cord. Spinal microglia stimulated by ATP contribute to tactile allodynia, a highly debilitating symptom of pain induced by nerve injury. Signalling between microglia and neurons is therefore an essential link in neuropathic pain transmission, but how this signalling occurs is unknown. Here we show that ATP-stimulated microglia cause a depolarizing shift in the anion reversal potential (E(anion)) in spinal lamina I neurons. This shift inverts the polarity of currents activated by GABA (gamma-amino butyric acid), as has been shown to occur after peripheral nerve injury. Applying brain-derived neurotrophic factor (BDNF) mimics the alteration in E(anion). Blocking signalling between BDNF and the receptor TrkB reverses the allodynia and the E(anion) shift that follows both nerve injury and administration of ATP-stimulated microglia. ATP stimulation evokes the release of BDNF from microglia. Preventing BDNF release from microglia by pretreating them with interfering RNA directed against BDNF before ATP stimulation also inhibits the effects of these cells on the withdrawal threshold and E(anion). Our results show that ATP-stimulated microglia signal to lamina I neurons, causing a collapse of their transmembrane anion gradient, and that BDNF is a crucial signalling molecule between microglia and neurons. Blocking this microglia-neuron signalling pathway may represent a therapeutic strategy for treating neuropathic pain.},

keywords = {},

pubstate = {published},

tppubtype = {article}

}