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.
Highlights
TAR DNA binding protein 43 is a DNA/RNA binding protein predominantly localized in the nucleus of cells [1]
Because of TDP43 proteinopathy, amyotrophic lateral sclerosis (ALS) and frontotemporal lobar degeneration (FTLD) are recognized as a disease continuum [7], but the same TDP43 alterations can be observed in other disorders such as Alzheimer’s disease (AD), Parkinson’s disease (PD), and vascular dementia [1, 8, 9]
We report for the first time to our knowledge a mouse monoclonal full-length antibody generated against the RRM1 domain of TDP43 that recognized cytoplasmic TDP43 species in cellular systems in mouse models and in human samples
Summary
TAR DNA binding protein 43 ( known as TDP43) is a DNA/RNA binding protein predominantly localized in the nucleus of cells [1]. Mislocalization and accumulation of hyperphosphorylated, fragmented, and ubiquitinated forms of this protein in the cytoplasm of neurons are known as TDP43 proteinopathy, a pathological hallmark of amyotrophic lateral sclerosis (ALS) and frontotemporal lobar degeneration (FTLD) [2, 3]. Despite different efforts in studying TDP43 during the pathological events, it remains unclear why and how TDP43 mislocalizes and accumulates in the cytoplasm. Once it starts to accumulate in the cytoplasm, it undoubtedly acquires cytotoxic properties [10]. For this reason, therapeutic approaches aimed to reduce cytoplasmic TDP43 accumulation are being considered [11, 12]. In the field of ALS, immunotherapies against SOD1 protein, involved in familial forms of the disease, have been developed and tested on cellular and mouse models, with encouraging results [15,16,17,18,19,20,21]
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