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The majority of preclinical studies in ALS have relied on transgenic models with overexpression of mutant human superoxide dismutase 1 (SOD1), widely regarded to have failed in terms of translation of therapeutic effects. However, there are still no widely accepted models of other genetic subtypes of ALS. The majority of patients show ubiquitinated cytoplasmic inclusions of TAR DNA binding protein of 43 kilodaltons (TDP-43) in spinal motor neurons at the end stage of disease and a small proportion have mutations in TARDBP, the gene encoding TDP-43. TDP-43 transgenic mouse models have been produced, but have not been widely adopted. Here, we characterised one of these models available from the Jackson Laboratory in detail. Compared to TDP-43WT mice, TDP-43Q331K mice had 43% less hindlimb muscle mass at 6 months and a 73% reduction in hindlimb compound muscle action potential at 8 months of age. Rotarod and gait analysis indicated motor system decline with elevated weight gain. At the molecular level, the lack of TDP-43 cellular pathology was confirmed with a surprising increase in nuclear TDP-43 in motor neurons. Power analysis indicated group sizes of 12–14 mice are needed to detect 10–20% changes in measured parameters with a power of 80%, providing valid readouts for preclinical testing. Overall, this model may represent a useful component of multi-model pre-clinical therapeutic studies for ALS. [ABSTRACT FROM AUTHOR]

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. [ABSTRACT FROM AUTHOR]