Female sex mitigates motor and behavioural phenotypes in TDP-43Q331K knock-in mice

Abstract

Amyotrophic lateral sclerosis (ALS) and frontotemporal dementia (FTD) are overlapping neurodegenerative disorders. ALS is more commonly seen in men than women and the same may be the case for FTD. Preclinical models demonstrating sex-specific vulnerability may help to understand female resistance to ALS-FTD and thereby identify routes to therapy. We previously characterised a TDP-43Q331K knock-in mouse, which demonstrated behavioural phenotypes reminiscent of ALS-FTD in males. Here we present our behavioural observations of female TDP-43Q331K mutants. Female TDP-43Q331K knock-in mice displayed increased weight relative to wild-type and increased food intake at 20 months of age, much later than previously observed in male mutants. Spontaneous digging behaviour was initially normal and only declined in mutants in the second year of life. Gait analysis using Catwalk (https://www.noldus.com/catwalk-xt) found significant deficits in the second year of life, while nocturnal running behaviour was attenuated from ~ 250 days of life. These results indicate that while female TDP-43Q331K knock-in mice do display progressive behavioural phenotypes, these are less severe than we previously noted in male mutants. Further studies of male and female TDP-43Q331K knock-in mice may help to unravel the mechanisms underlying sex-specific vulnerability in ALS-FTD.

Opposing roles of p38α-mediated phosphorylation and arginine methylation in driving TDP-43 proteinopathy

“…Thus, we first asked whether p38α modulates the formation of insoluble TDP-43 aggregates in human neuronal SH-SY5Y cells. Increased expression of wild-type or ALS-linked TDP-43 variants elicits ALS-like phenotypes in various in vitro and in vivo models (Arnold et al, 2013;Watkins et al, 2020;Wobst et al, 2017;Xu et al, 2011). Indeed, elevated expression of wild-type TDP-43 is connected with FTD (Gitcho et al, 2009) and disease-linked TDP-43 aggregation is proposed to increase TDP-43 expression due to loss of TDP-43 autoregulation (Gasset- Rosa et al, 2019;Polymenidou et al, 2011).…”

Sexually dimorphic RNA helicases DDX3X and DDX3Y differentially regulate RNA metabolism through phase separation

“…SGs, which are composed of RNAs and proteins and form part of the stress response, are correlated with changes to mRNA metabolism, including translational repression (Kimball et al, 2003;Moon et al, 2019). Dysregulation of SGs has been implicated in a wide range of human disorders, including cardiomyopathy, Alzheimer's disease, and amyotrophic lateral sclerosis (ALS), many of which present with varying degrees of sex-biased incidences, progressions, and outcomes (Ash et al, 2014;Baradaran-Heravi et al, 2020;Ferretti et al, 2018;Manjaly et al, 2010;McCombe and Henderson, 2010;Meyer et al, 2014;Schneider et al, 2020;Watkins et al, 2020). Additionally, DDX3X mutations can lead to DDX3X syndrome, a disorder that accounts for 1%-3% of intellectual disability cases and is more prevalent in females than in males (Iossifov et al, 2014;Lennox et al, 2020;Ruzzo et al, 2019;Scala et al, 2019;Snijders Blok et al, 2015;Wang et al, 2018b).…”

A bioisostere of Dimebon/Latrepirdine delays the onset and slows the progression of pathology in FUS transgenic mice

“…CatWalk is an effective combination of hardware and software in an experimental system designed for simultaneous analysis of multiple parameters of rodent gait 53,54 . It has been successfully used to assess changes in animal motor function in several transgenic models of neurodegenerative diseases 55–58 . Here, this system was used for the first time to detect motor deficiency in transgenic mice modeling ALS‐FUS by neuronal expression of pathogenic truncated form of human FUS protein 33 …”