In vivo analysis of aggregation propensity of low levels of mislocalized TDP-43 on cytopathological and behavioral phenotype of ALS/FTLD.
Neurosci Res
; 193: 41-51, 2023 Aug.
Article
em En
| MEDLINE
| ID: mdl-36804599
ABSTRACT
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.
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Texto completo:
1
Coleções:
01-internacional
Base de dados:
MEDLINE
Assunto principal:
Degeneração Lobar Frontotemporal
/
Esclerose Lateral Amiotrófica
Limite:
Animals
/
Humans
Idioma:
En
Revista:
Neurosci Res
Ano de publicação:
2023
Tipo de documento:
Article