Neurodegenerative Disease Tauopathies

Creekmore, Benjamin C.; Watanabe, Ryohei; Lee, Edward B.

doi:10.1146/annurev-pathmechdis-051222-120750

Cited by 16 publications

(2 citation statements)

References 132 publications

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“…p97 is an extensively characterized ubiquitously expressed protein involved in fundamental cellular processes, such as the degradation of proteins associated with the endoplasmic reticulum (ER) (ERAD) 79 , autophagy 80 , and it is also an important player in the proteostasis of aggregates in Parkinson’s disease 46,81,82 . Indeed, p97 has been shown to protect against the proteopathic spread of pathogenic aggregates in animal models 83 .…”

Section: Discussionmentioning

confidence: 99%

Specific proteolysis mediated by a p97-directed proteolysis-targeting chimera (PROTAC)

Salinas-Rebolledo,

Blesa,

Valenzuela-Nieto

et al. 2024

Preprint

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The p97 protein is a member of the AAA + family of ATPases. It is a mechanoenzyme that uses energy from ATP hydrolysis to promote protein unfolding and segregation actively. The unfolded products of p97 are presented to the 26S Proteasome for degradation. p97 substrate recognition is mediated by adaptors, which interact with substrates directly or indirectly through ubiquitin modifications, resulting in substrate funnelling into the central pore of the p97 hexamer and unfolding. We have engineered synthetic adaptors to target specific substrates to p97, using the extraordinary intracellular binding capabilities of camelid nanobodies fused to the UBX domain of the p97 Adapter FAF1. In such a way, we created a p97-directed proteolysis-targeting chimera (PROTAC), representing a unique E3 ubiquitin ligase-independent strategy to promote specific proteolysis.

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Section: Discussionmentioning

confidence: 99%

Specific proteolysis mediated by a p97-directed proteolysis-targeting chimera (PROTAC)

Salinas-Rebolledo,

Blesa,

Valenzuela-Nieto

et al. 2024

Preprint

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“…Although the microtubule-associated protein Tau has been described for nearly 50 years [1] and its role in neurodegenerative dementias has been firmly established [2,3], the physiological processes within neurons requiring this protein are less understood. Animal models of Alzheimer's disease, Frontotemporal Dementias, and other Tauopathies have contributed significantly to understanding their apparently varied pathogenic mechanisms.…”

Section: Introductionmentioning

confidence: 99%

Choline Metabolites Reverse Differentially the Habituation Deficit and Elevated Memory of Tau Null Drosophila

Zerva,

Triantafylloudis,

Paspaliaris

et al. 2024

Cells

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Impaired neuronal plasticity and cognitive decline are cardinal features of Alzheimer’s disease and related Tauopathies. Aberrantly modified Tau protein and neurotransmitter imbalance, predominantly involving acetylcholine, have been linked to these symptoms. In Drosophila, we have shown that dTau loss specifically enhances associative long-term olfactory memory, impairs foot shock habituation, and deregulates proteins involved in the regulation of neurotransmitter levels, particularly acetylcholine. Interestingly, upon choline treatment, the habituation and memory performance of mutants are restored to that of control flies. Based on these surprising results, we decided to use our well-established genetic model to understand how habituation deficits and memory performance correlate with different aspects of choline physiology as an essential component of the neurotransmitter acetylcholine, the lipid phosphatidylcholine, and the osmoregulator betaine. The results revealed that the two observed phenotypes are reversed by different choline metabolites, implying that they are governed by different underlying mechanisms. This work can contribute to a broader knowledge about the physiologic function of Tau, which may be translated into understanding the mechanisms of Tauopathies.

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Programmed cell death: molecular mechanisms, biological functions, diseases, and therapeutic targets

Qian,

Long,

Tan

et al. 2024

MedComm

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Programmed cell death represents a precisely regulated and active cellular demise, governed by a complex network of specific genes and proteins. The identification of multiple forms of programmed cell death has significantly advanced the understanding of its intricate mechanisms, as demonstrated in recent studies. A thorough grasp of these processes is essential across various biological disciplines and in the study of diseases. Nonetheless, despite notable progress, the exploration of the relationship between programmed cell death and disease, as well as its clinical application, are still in a nascent stage. Therefore, further exploration of programmed cell death and the development of corresponding therapeutic methods and strategies holds substantial potential. Our review provides a detailed examination of the primary mechanisms behind apoptosis, autophagy, necroptosis, pyroptosis, and ferroptosis. Following this, the discussion delves into biological functions and diseases associated dysregulated programmed cell death. Finally, we highlight existing and potential therapeutic targets and strategies focused on cancers and neurodegenerative diseases. This review aims to summarize the latest insights on programmed cell death from mechanisms to diseases and provides a more reliable approach for clinical transformation.

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Neurodegenerative Disease Tauopathies

Cited by 16 publications

References 132 publications

Specific proteolysis mediated by a p97-directed proteolysis-targeting chimera (PROTAC)

Specific proteolysis mediated by a p97-directed proteolysis-targeting chimera (PROTAC)

Choline Metabolites Reverse Differentially the Habituation Deficit and Elevated Memory of Tau Null Drosophila

Programmed cell death: molecular mechanisms, biological functions, diseases, and therapeutic targets

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