Abstract
Amyotrophic lateral sclerosis (ALS) attacks the corticomotor system, with motor cortex function affected early in disease. Younger females have a lower relative risk of succumbing to ALS than males and older females, implicating a role for female sex hormones in disease progression. However, the mechanisms driving this dimorphic incidence are still largely unknown. We endeavoured to determine if estrogen mitigates disease progression and pathogenesis, focussing upon the dendritic spine as a site of action. Using two-photon live imaging we identify, in the prpTDP-43A315T mouse model of ALS, that dendritic spines in the male motor cortex have a reduced capacity for remodelling than their wild-type controls. In contrast, females show higher capacity for remodelling, with peak plasticity corresponding to highest estrogen levels during the estrous cycle. Estrogen manipulation through ovariectomies and estrogen replacement with 17β estradiol in vivo was found to significantly alter spine density and mitigate disease severity. Collectively, these findings reveal that synpatic plasticity is reduced in ALS, which can be amelioriated with estrogen, in conjuction with improved disease outcomes.
Highlights
Amyotrophic lateral sclerosis (ALS) exists on a disease spectrum with frontotemporal dementia (FTD), sharing pathological and genetic features, and clinical overlap [1–3]
The the prpTDP-43A315T (TDP-43) mouse carries a familial ALS mutation, and develops an ALS-FTD spectrum phenotype of motor and cognitive dysfunction [29, 44, 47], with the P60 timepoint representing a presymptomatic stage in TDP-43 mice, with symptom onset occurring at approximately P90 [29, 44]
We identify for the first time that structural plasticity at the dendritic spine is impaired presymptomatically in the motor cortex of male TDP-43 mice, as well as in female TDP-43 mice experiencing baseline estrogen levels
Summary
Amyotrophic lateral sclerosis (ALS) exists on a disease spectrum with frontotemporal dementia (FTD), sharing pathological and genetic features, and clinical overlap [1–3]. In ALS, the corticomotor system rapidly degenerates leaving other regions relatively spared [4–6]. Whilst once believed to be primarily neuromuscular, ALS is characterised by a large neurodegenerative component within the brain. One of the earliest detectable clinical markers of ALS is hyperexcitability within the motor cortex, with this pathophysiological change able to spread neuronal dysfunction, manifesting as excitotoxicity, throughout the corticomotor system [8–12]. Why the corticomotor system succumbs to pathological TDP-43 in ALS and what drives this pathology remains elusive. It is imperative to answer these questions to devise the targeted therapeutic interventions that these diseases so desperately need
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