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Misfolding of the prion protein (PrP) is responsible for devastating neurological disorders in humans and other mammals. An unresolved problem in the field is unraveling the mechanisms governing PrP conformational dynamics, misfolding, and the cellular mechanism leading to neurodegeneration. The variable susceptibility of mammals to prion diseases is a natural resource that can be exploited to understand the conformational dynamics of PrP. Here we present a new fly model expressing human PrP with new, robust phenotypes in brain neurons and the eye. By using comparable attP2 insertions, we demonstrated the heightened toxicity of human PrP compared to rodent PrP along with a specific interaction with the amyloid-β peptide. By using this new model, we started to uncover the intrinsic (sequence/structure) and extrinsic (interactions) factors regulating PrP toxicity. We described PERK (officially known as EIF2AK3 in humans) and activating transcription factor 4 (ATF4) as key in the cellular mechanism mediating the toxicity of human PrP and uncover a key new protective activity for 4E-BP (officially known as Thor in Drosophila and EIF4EBP2 in humans), an ATF4 transcriptional target. Lastly, mutations in human PrP (N159D, D167S, N174S) showed partial protective activity, revealing its high propensity to misfold into toxic conformations.

Alzheimer’s disease (AD) is the most prevalent of a large group of related proteinopathies forwhich there is currently no cure. Here, we used Drosophila to explore a strategy to block Aβ42 neurotoxicity through engineering of the Heat shock protein 70 (Hsp70), a chaperone that has demonstrated neuroprotective activity against several intracellular amyloids. To target its protective activity against extracellular Aβ42, we added a signal peptide to Hsp70. This secreted form of Hsp70 (secHsp70) suppresses Aβ42 neurotoxicity in adult eyes, reduces cell death, protects the structural integrity of adult neurons, alleviates locomotor dysfunction, and extends lifespan. SecHsp70 binding to Aβ42 through its holdase domain is neuroprotective, but its ATPase activity is not required in the extracellular space. Thus, the holdase activity of secHsp70 masks Aβ42 neurotoxicity by promoting the accumulation of nontoxic aggregates. Combined with other approaches, this strategy may contribute to reduce the burden of AD and other extracellular proteinopathies.

Alzheimer's disease (AD) is the most prevalent of a large group of related proteinopathies for which there is currently no cure. Here, we used Drosophila to explore a strategy to block A beta 42 neurotoxicity through engineering of the Heat shock protein 70 (Hsp70), a chaperone that has demonstrated neuroprotective activity against several intracellular amyloids. To target its protective activity against extracellular A beta 42, we added a signal peptide to Hsp70. This secreted form of Hsp70 (secHsp70) suppresses A beta 42 neurotoxicity in adult eyes, reduces cell death, protects the structural integrity of adult neurons, alleviates locomotor dysfunction, and extends lifespan. SecHsp70 binding to A beta 42 through its holdase domain is neuroprotective, but its ATPase activity is not required in the extracellular space. Thus, the holdase activity of secHsp70 masks A beta 42 neurotoxicity by promoting the accumulation of nontoxic aggregates. Combined with other approaches, this strategy may contribute to reduce the burden of AD and other extracellular proteinopathies.

Alzheimer's disease (AD) is the most prevalent of a large group of related proteinopathies for which there is currently no cure. Here, we used Drosophila to explore a strategy to block Aβ42 neurotoxicity through engineering of the Heat shock protein 70 (Hsp70), a chaperone that has demonstrated neuroprotective activity against several intracellular amyloids. To target its protective activity against extracellular Aβ42, we added a signal peptide to Hsp70. This secreted form of Hsp70 (secHsp70) suppresses Aβ42 neurotoxicity in adult eyes, reduces cell death, protects the structural integrity of adult neurons, alleviates locomotor dysfunction, and extends lifespan. SecHsp70 binding to Aβ42 through its holdase domain is neuroprotective, but its ATPase activity is not required in the extracellular space. Thus, the holdase activity of secHsp70 masks Aβ42 neurotoxicity by promoting the accumulation of nontoxic aggregates. Combined with other approaches, this strategy may contribute to reduce the burden of AD and other extracellular proteinopathies.

Misfolded conformations of the prion protein (PrP) are responsible for devastating neurological disorders in humans and mammals. An unresolved problem is unraveling the mechanisms governing PrP conformational dynamics, misfolding, and the cellular mechanism leading to neurodegeneration. The variable susceptibility of mammals to prion diseases can be exploited to understand the conformational dynamics of PrP. Here we present a new fly model expressing human PrP with robust phenotypes in brain neurons and the eye. Using comparable attP2 insertions, we demonstrate the heightened toxicity of human PrP compared to that of mouse and hamster PrP along with a specific interaction with the amyloid-beta peptide. Using this new highly toxic new model, we started to uncover the intrinsic (sequence / structure) and extrinsic (interactions) factors regulating PrP toxicity. As extrinsic factors, we describe the importance of the PERK - ATF4 branch of the unfolded protein response as a key cellular mechanism mediating the toxicity of human PrP. For intrinsic factors, we introduced point mutations in human PrP (N159D, D167S, N174S) that were partially protective, revealing its high propensity to misfold into toxic conformations. Competing Interest Statement The authors have declared no competing interest.

The purpose of this study was twofold: to analyse physical performance fluctuations throughout match play in women's handball; and to investigate whether physical performance fluctuations are affected by contextual factors (i.e., level of the opponent and playing positions). Twenty-two female players from the Spanish 2 Division were monitored across 13 matches. Each match was divided into 5 min fixed phases. Total distance (TD), high-speed running (HSR) and PlayerLoad (PL) were collected using a local positioning system. The highest values of TD, HSR and PL were registered during the first 5 min phase of the match (p < 0.05, moderate-large effects), while the lowest values of TD and PL were registered in the last phase of the first half and for HSR in the last phase of the match (p < 0.001, large effects). Regarding level of the opponent, low-level teams elicited higher TD in the first 10 min of the match (p < 0.05, moderate effects). Conversely, matches involving high-level teams registered more TD and PL in the last phase of the match (p < 0.05, moderate effects). In relation to playing positions, wings showed the highest physical performance in all 5 min phases of the match, whereas the pivots showed the lowest physical performance. In the present study the physical performance decreased throughout the match and the fluctuations were strongly affected by the level of the opponent and playing positions. Therefore, handball coaches should incorporate strategies to mitigate fatigue within and between halves.