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Monoclonal full-length antibody against TAR DNA binding protein 43 reduces related proteinopathy in neurons.

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-?B 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.

SUBMITTER: Pozzi S

PROVIDER: S-EPMC7710295 | biostudies-literature | 2020 Nov

REPOSITORIES: biostudies-literature

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Monoclonal full-length antibody against TAR DNA binding protein 43 reduces related proteinopathy in neurons.

Pozzi Silvia S Codron Philippe P Soucy Geneviève G Renaud Laurence L Cordeau Pierre Junior PJ Dutta Kallol K Bareil Christine C Julien Jean-Pierre JP

JCI insight 20201105 21

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 ...[more]

PMID: 33021970

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Project description:Amyotrophic lateral sclerosis (ALS) is a fatal and incurable neurodegenerative disease caused by motor neuron loss, resulting in muscle wasting, paralysis and eventual death. A key pathological feature of ALS is cytoplasmically mislocalized and aggregated TDP-43 protein in >95% of cases, which is considered to have prion-like properties. Historical studies have predominantly focused on genetic forms of ALS, which represent ?10% of cases, leaving the remaining 90% of sporadic ALS relatively understudied. Additionally, the role of astrocytes in ALS and their relationship with TDP-43 pathology is also not currently well understood. We have therefore used highly enriched human induced pluripotent stem cell (iPSC)-derived motor neurons and astrocytes to model early cell type-specific features of sporadic ALS. We first demonstrate seeded aggregation of TDP-43 by exposing human iPSC-derived motor neurons to serially passaged sporadic ALS post-mortem tissue (spALS) extracts. Next, we show that human iPSC-derived motor neurons are more vulnerable to TDP-43 aggregation and toxicity compared with their astrocyte counterparts. We demonstrate that these TDP-43 aggregates can more readily propagate from motor neurons into astrocytes in co-culture paradigms. We next found that astrocytes are neuroprotective to seeded aggregation within motor neurons by reducing (mislocalized) cytoplasmic TDP-43, TDP-43 aggregation and cell toxicity. Furthermore, we detected TDP-43 oligomers in these spALS spinal cord extracts, and as such demonstrated that highly purified recombinant TDP-43 oligomers can reproduce this observed cell-type specific toxicity, providing further support to a protein oligomer-mediated toxicity hypothesis in ALS. In summary, we have developed a human, clinically relevant, and cell-type specific modelling platform that recapitulates key aspects of sporadic ALS and uncovers both an initial neuroprotective role for astrocytes and the cell type-specific toxic effect of TDP-43 oligomers.

Project description:GGGGCC repeat expansions of C9ORF72 represent the most common genetic variant of amyotrophic lateral sclerosis (ALS) and frontotemporal dementia. We and others have proposed that RNA transcribed from the repeat sequence is toxic via sequestration of RNA-binding factors. Both GGGGCC-repeat (sense) and CCCCGG-repeat (antisense) molecules are detectable by fluorescence in situ hybridisation as RNA foci, but their relative expression pattern within the CNS and contribution to disease has not been determined. Blinded examination of CNS biosamples from ALS patients with a repeat expansion of C9ORF72 showed that antisense foci are present at a significantly higher frequency in cerebellar Purkinje neurons and motor neurons, whereas sense foci are present at a significantly higher frequency in cerebellar granule neurons. Consistent with this, inclusions containing sense or antisense derived dipeptide repeat proteins were present at significantly higher frequency in cerebellar granule neurons or motor neurons, respectively. Immunohistochemistry and UV-crosslinking studies showed that sense and antisense RNA molecules share similar interactions with SRSF2, hnRNP K, hnRNP A1, ALYREF, and hnRNP H/F. Together these data suggest that, although sense and antisense RNA molecules might be expected to be equally toxic via their shared protein binding partners, distinct patterns of expression in various CNS neuronal populations could lead to relative differences in their contribution to the pathogenesis of neuronal injury. Moreover in motor neurons, which are the primary target of pathology in ALS, the presence of antisense foci (? (2), p < 0.00001) but not sense foci (? (2), p = 0.75) correlated with mislocalisation of TDP-43, which is the hallmark of ALS neurodegeneration. This has implications for translational approaches to C9ORF72 disease, and furthermore interacting RNA-processing factors and transcriptional activators responsible for antisense versus sense transcription might represent novel therapeutic targets.

Project description:To better understand clinical and neuropathological features of TDP-43 proteinopathies, data were analyzed from autopsied research volunteers who were followed in the National Alzheimer's Coordinating Center (NACC) data set. All subjects (n = 495) had autopsy-proven TDP-43 proteinopathy as an inclusion criterion. Subjects underwent comprehensive longitudinal clinical evaluations yearly for 6.9 years before death on average. We tested whether an unsupervised clustering algorithm could detect coherent groups of TDP-43 immunopositive cases based on age at death and extensive neuropathologic data. Although many of the brains had mixed pathologies, four discernible clusters were identified. Key differentiating features were age at death and the severity of comorbid Alzheimer's disease neuropathologic changes (ADNC), particularly neuritic amyloid plaque densities. Cluster 1 contained mostly cases with a pathologic diagnosis of frontotemporal lobar degeneration (FTLD-TDP), consistent with enrichment of frontotemporal dementia clinical phenotypes including appetite/eating problems, disinhibition and primary progressive aphasia (PPA). Cluster 2 consisted of elderly limbic-predominant age-related TDP-43 encephalopathy (LATE-NC) subjects without severe neuritic amyloid plaques. Subjects in Cluster 2 had a relatively slow cognitive decline. Subjects in both Clusters 3 and 4 had severe ADNC + LATE-NC; however, Cluster 4 was distinguished by earlier disease onset, swifter disease course, more Lewy body pathology, less neocortical TDP-43 proteinopathy, and a suggestive trend in a subgroup analysis (n = 114) for increased C9orf72 risk SNP rs3849942 T allele (Fisher's exact test p value = 0.095). Overall, clusters enriched with neocortical TDP-43 proteinopathy (Clusters 1 and 2) tended to have lower levels of neuritic amyloid plaques, and those dying older (Clusters 2 and 3) had far less PPA or disinhibition, but more apathy. Indeed, 98% of subjects dying past age 85 years lacked clinical features of the frontotemporal dementia syndrome. Our study revealed discernible subtypes of LATE-NC and underscored the importance of age of death for differentiating FTLD-TDP and LATE-NC.

Dataset Information

Monoclonal full-length antibody against TAR DNA binding protein 43 reduces related proteinopathy in neurons.

Publications

Monoclonal full-length antibody against TAR DNA binding protein 43 reduces related proteinopathy in neurons.

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