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Parkinson’s disease (PD) is closely linked to α-synuclein (α-syn) misfolding and accumulation in Lewy bodies. The PDZ serine protease HTRA1 degrades fibrillar tau, which is associated with Alzheimer’s disease, and inactivating mutations to mitochondrial HTRA2 are implicated in PD. Here, we report that HTRA1 inhibits aggregation of α-syn as well as FUS and TDP-43, which are implicated in amyotrophic lateral sclerosis (ALS) and frontotemporal dementia. The protease domain of HTRA1 is necessary and sufficient for inhibiting aggregation, yet this activity is proteolytically-independent. Further, HTRA1 disaggregates preformed α-syn fibrils, rendering them incapable of seeding aggregation of endogenous α-syn, while reducing HTRA1 expression promotes α-syn seeding. HTRA1 remodels α-syn fibrils by targeting the NAC domain, the key domain catalyzing α-syn amyloidogenesis. Finally, HTRA1 detoxifies α-syn fibrils and prevents formation of hyperphosphorylated α-syn accumulations in primary neurons. Our findings suggest that HTRA1 may be a therapeutic target for a range of neurodegenerative disorders.The PDZ serine protease HTRA1 degrades fibrillar tau, which is associated with Alzheimer’s disease. Here the authors report that HTRA1 inhibits aggregation of α-syn as well as FUS and TDP-43, which are implicated in amyotrophic lateral sclerosis (ALS) and frontotemporal dementia. [ABSTRACT FROM AUTHOR]

Reproduction is an energetically expensive activity for both sexes. However, if males and females differ in their annual timing of reproduction, such that peak investment for one sex occurs during a more resource-limited period, there is an opportunity for sex-specific selection to act on the acquisition of energetic resources. Both male and female North American red squirrels (Tamiasciurus hudsonicus) cache conifer cones, although males typically have larger caches than females. Peak energetic investment in reproduction occurs for males during the mating season in winter and early spring (when squirrels rely almost exclusively on cached resources) and for females during lactation (which can align with fresh food availability). We provide evidence that suggests sex differences in cache size are likely driven by a stronger positive connection between cached resources and components of fitness for males than for females. Specifically, males with larger caches have greater siring success than males with smaller caches, whereas for females, only early breeding females experience a positive effect of cache size on the number of recruits produced. We also show that males sire pups and females give birth earlier in the year if they have larger caches compared with squirrels of the same sex with smaller caches. Sexual selection can thus extend beyond traits directly connected to mating behavior, and can act on traits related to acquiring resources needed to fuel reproduction that are expressed months or years in advance of breeding efforts. Significance statement: The timing and energetic requirements of reproduction are often different for males and females which could drive different life history strategies between the sexes. Red squirrels in the southwest Yukon, Canada cache white spruce cones in autumn, which serve as their primary food source until fresh food becomes available during summer. We measured the size of squirrel caches and subsequently monitored their reproduction to test whether the influence of stored food differs for males and females. We confirmed that males have larger caches than females and show that this is likely driven by a stronger positive association of cache size and components of fitness for males than for females. These findings highlight that the strength of selection can differ on the homologous traits of males and females leading to sex-specific extended phenotypes. [ABSTRACT FROM AUTHOR]