In vivo analysis of aggregation propensity of low levels of mislocalized TDP-43 on cytopathological and behavioral phenotype of ALS/FTLD

• Published in: Neuroscience research 2023-08, Vol.193, p.41-51
• Main Authors: Wada, Hideki, Hikiami, Ryota, Kusui, Makiko, Minamiyama, Sumio, Asada-Utsugi, Megumi, Shodai, Akemi, Muramatsu, Shin-ichi, Morimura, Toshifumi, Urushitani, Makoto
• Format: Article
• Language: English
• Subjects: Aggregates; Amyotrophic lateral sclerosis (ALS); Amyotrophic Lateral Sclerosis - genetics; Animals; Cerebral Cortex - metabolism; DNA-Binding Proteins - metabolism; Frontotemporal Lobar Degeneration - genetics; Frontotemporal lobar degeneration FTLD; Humans; Mice; Mice, Transgenic; Neurons - metabolism; Nucleus localizing signal (NLS); TAR DNA-binding protein 43kDa (TDP-43)
• ISSN: 0168-0102; 1872-8111
• DOI: 10.1016/j.neures.2023.02.006

Mislocalization and aggregate formation of TAR DNA-biding protein of 43kD (TDP-43) in the cytoplasm are signatures of amyotrophic lateral sclerosis(ALS) and frontotemporal lobar degeneration (FTLD). However, the role of two cytopathologies in ALS/FTLD pathogenesis is unclear. This study aims to elucidate the difference in their causality of TDP-43 in ALS/FTLD in vivo, using transgenic mice expressing human TDP-43 with defective nuclear localizing signals in neurons (Cyto-TDP) and those with aggregation propensity (Cyto-aggTDP). The expression levels of both proteins are less than half of endogenous TDP-43. Despite the low amount of Cyto-aggTDP, the TDP-43 phosphorylation is more evident than Cyto-TDP. Histopathological study showed accelerated astrogliosis in the anterior cerebral cortex of both mice. Cyto-aggTDP mice demonstrated significant but faint loss of neurons in the perirhinal(PERI) and ectorhinal(ECT) areas and higher Iba1-staining in the spinal cord than aged control. Despite the lack of locomotor dysfunctions in both mice, the open-field test showed enhanced exploratory behavior, indicating that the perpetual mislocalization of TDP-43 may suffice to trigger FTLD behavior. Besides, the aggregation propensity of TDP-43 promotes phosphorylation, but its role in the clinicopathological phenotype may not be primary. •Low level mislocalized or aggregate-prone TDP-43 expressing mice were generated.•Both mice showed no neuronal loss in the spinal cord, but gliosis in the cortex.•Both mice showed no motor symptoms, but had anxiety-like symptoms.•FTLD precedes ALS by Low levels of mislocalized TDP-43 in mice despite aggregates.