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000259006 1001_ $$0P:(DE-2719)2812261$$aRiemenschneider, Henrick$$b0$$eFirst author$$udzne
000259006 245__ $$aTargeting the glycine-rich domain of TDP-43 with antibodies prevents its aggregation in vitro and reduces neurofilament levels in vivo.
000259006 260__ $$aLondon$$bBiomed Central$$c2023
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000259006 520__ $$aCytoplasmic aggregation and concomitant nuclear clearance of the RNA-binding protein TDP-43 are found in ~ 90% of cases of amyotrophic lateral sclerosis and ~ 45% of patients living with frontotemporal lobar degeneration, but no disease-modifying therapy is available. Antibody therapy targeting other aggregating proteins associated with neurodegenerative disorders has shown beneficial effects in animal models and clinical trials. The most effective epitopes for safe antibody therapy targeting TDP-43 are unknown. Here, we identified safe and effective epitopes in TDP-43 for active and potential future passive immunotherapy. We prescreened 15 peptide antigens covering all regions of TDP-43 to identify the most immunogenic epitopes and to raise novel monoclonal antibodies in wild-type mice. Most peptides induced a considerable antibody response and no antigen triggered obvious side effects. Thus, we immunized mice with rapidly progressing TDP-43 proteinopathy ('rNLS8' model) with the nine most immunogenic peptides in five pools prior to TDP-43ΔNLS transgene induction. Strikingly, combined administration of two N-terminal peptides induced genetic background-specific sudden lethality in several mice and was therefore discontinued. Despite a strong antibody response, no TDP-43 peptide prevented the rapid body weight loss or reduced phospho-TDP-43 levels as well as the profound astrogliosis and microgliosis in rNLS8 mice. However, immunization with a C-terminal peptide containing the disease-associated phospho-serines 409/410 significantly lowered serum neurofilament light chain levels, indicative of reduced neuroaxonal damage. Transcriptomic profiling showed a pronounced neuroinflammatory signature (IL-1β, TNF-α, NfκB) in rNLS8 mice and suggested modest benefits of immunization targeting the glycine-rich region. Several novel monoclonal antibodies targeting the glycine-rich domain potently reduced phase separation and aggregation of TDP-43 in vitro and prevented cellular uptake of preformed aggregates. Our unbiased screen suggests that targeting the RRM2 domain and the C-terminal region of TDP-43 by active or passive immunization may be beneficial in TDP-43 proteinopathies by inhibiting cardinal processes of disease progression.
000259006 536__ $$0G:(DE-HGF)POF4-352$$a352 - Disease Mechanisms (POF4-352)$$cPOF4-352$$fPOF IV$$x0
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000259006 650_2 $$2MeSH$$aAnimals
000259006 650_2 $$2MeSH$$aMice
000259006 650_2 $$2MeSH$$aAntibodies, Monoclonal
000259006 650_2 $$2MeSH$$aEpitopes
000259006 650_2 $$2MeSH$$aImmunization
000259006 650_2 $$2MeSH$$aIntermediate Filaments
000259006 650_2 $$2MeSH$$aNF-kappa B
000259006 650_7 $$2NLM Chemicals$$aAntibodies, Monoclonal
000259006 650_7 $$2Other$$aAggregation
000259006 650_7 $$2Other$$aAmyotrophic lateral sclerosis
000259006 650_7 $$2Other$$aFrontotemporal dementia
000259006 650_7 $$2Other$$aImmunotherapy
000259006 650_7 $$2Other$$aNeurodegeneration
000259006 650_7 $$2Other$$aPhase separation
000259006 650_7 $$2Other$$aTDP-43
000259006 650_7 $$2NLM Chemicals$$aEpitopes
000259006 650_7 $$2NLM Chemicals$$aNF-kappa B
000259006 650_7 $$2NLM Chemicals$$aTDP-43 protein, mouse
000259006 7001_ $$0P:(DE-2719)9001596$$aSimonetti, Francesca$$b1$$eFirst author$$udzne
000259006 7001_ $$aSheth, Udit$$b2
000259006 7001_ $$0P:(DE-2719)9001378$$aKatona, Eszter$$b3$$eFirst author$$udzne
000259006 7001_ $$aRoth, Stefan$$b4
000259006 7001_ $$aHutten, Saskia$$b5
000259006 7001_ $$0P:(DE-2719)2812127$$aFarny, Daniel$$b6$$udzne
000259006 7001_ $$0P:(DE-2719)2811691$$aMichaelsen, Meike$$b7$$udzne
000259006 7001_ $$0P:(DE-HGF)0$$aNuscher, Brigitte$$b8
000259006 7001_ $$aSchmidt, Michael K$$b9
000259006 7001_ $$0P:(DE-HGF)0$$aFlatley, Andrew$$b10
000259006 7001_ $$aSchepers, Aloys$$b11
000259006 7001_ $$aGruijs da Silva, Lara A$$b12
000259006 7001_ $$0P:(DE-2719)2811347$$aZhou, Qihui$$b13$$udzne
000259006 7001_ $$0P:(DE-2719)2810704$$aKlopstock, Thomas$$b14$$udzne
000259006 7001_ $$aLiesz, Arthur$$b15
000259006 7001_ $$0P:(DE-2719)2811333$$aArzberger, Thomas$$b16$$udzne
000259006 7001_ $$0P:(DE-2719)2810441$$aHerms, Jochen$$b17$$udzne
000259006 7001_ $$0P:(DE-2719)2812867$$aFeederle, Regina$$b18$$udzne
000259006 7001_ $$aGendron, Tania F$$b19
000259006 7001_ $$aDormann, Dorothee$$b20
000259006 7001_ $$0P:(DE-2719)2231621$$aEdbauer, Dieter$$b21$$eLast author
000259006 773__ $$0PERI:(DE-600)2715589-4$$a10.1186/s40478-023-01592-z$$gVol. 11, no. 1, p. 112$$n1$$p112$$tActa Neuropathologica Communications$$v11$$x2051-5960$$y2023
000259006 8564_ $$uhttps://actaneurocomms.biomedcentral.com/articles/10.1186/s40478-023-01592-z
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000259006 9201_ $$0I:(DE-2719)1110004$$kAG Edbauer$$lCell Biology of Neurodegeneration$$x0
000259006 9201_ $$0I:(DE-2719)5000080$$kAG Zhou$$lAdaptive Immunity in Neurodegeneration$$x1
000259006 9201_ $$0I:(DE-2719)1140013$$kNeuropathology / Brainbank$$lNeuropathology / Brainbank$$x2
000259006 9201_ $$0I:(DE-2719)1110001$$kAG Herms$$lTranslational Brain Research$$x3
000259006 9201_ $$0I:(DE-2719)1140004$$kAG Feederle$$lAntibody production$$x4
000259006 9201_ $$0I:(DE-2719)1111016$$kClinical Dementia Research München ; AG Levin$$lClinical Dementia Research München Levin$$x5
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