bims-lypmec 2023-06-11 papers

Neural Regen Res. 2023 Nov;18(11): 2370-2376

Enhancement of lysosome biogenesis as a potential therapeutic approach for neurodegenerative diseases.

Millions of people are suffering from Alzheimer's disease globally, but there is still no effective treatment for this neurodegenerative disease. Thus, novel therapeutic approaches for Alzheimer's disease are needed, which requires further evaluation of the regulatory mechanisms of protein aggregate degradation. Lysosomes are crucial degradative organelles that maintain cellular homeostasis. Transcription factor EB-mediated lysosome biogenesis enhances autolysosome-dependent degradation, which subsequently alleviates neurodegenerative diseases, including Alzheimer's disease, Parkinson's disease, and Huntington's disease. In this review, we start by describing the key features of lysosomes, including their roles in nutrient sensing and degradation, and their functional impairments in different neurodegenerative diseases. We also explain the mechanisms - especially the post-translational modifications - which impact transcription factor EB and regulate lysosome biogenesis. Next, we discuss strategies for promoting the degradation of toxic protein aggregates. We describe Proteolysis-Targeting Chimera and related technologies for the targeted degradation of specific proteins. We also introduce a group of LYsosome-Enhancing Compounds, which promote transcription factor EB-mediated lysosome biogenesis and improve learning, memory, and cognitive function in APP-PSEN1 mice. In summary, this review highlights the key aspects of lysosome biology, the mechanisms of transcription factor EB activation and lysosome biogenesis, and the promising strategies which are emerging to alleviate the pathogenesis of neurodegenerative diseases.

Keywords: Alzheimer’s disease; LYsosome-Enhancing Compounds; degradation; lysosome biogenesis; neurodegenerative diseases; post-translational modifications; protein aggregates; transcription factor EB

DOI: https://doi.org/10.4103/1673-5374.371346

Transl Neurodegener. 2023 Jun 08. 12(1): 29

Defective lysosomal acidification: a new prognostic marker and therapeutic target for neurodegenerative diseases.

Chih Hung Lo, Jialiu Zeng.

Lysosomal acidification dysfunction has been implicated as a key driving factor in the pathogenesis of neurodegenerative diseases, including Alzheimer's disease and Parkinson's disease. Multiple genetic factors have been linked to lysosomal de-acidification through impairing the vacuolar-type ATPase and ion channels on the organelle membrane. Similar lysosomal abnormalities are also present in sporadic forms of neurodegeneration, although the underlying pathogenic mechanisms are unclear and remain to be investigated. Importantly, recent studies have revealed early occurrence of lysosomal acidification impairment before the onset of neurodegeneration and late-stage pathology. However, there is a lack of methods for organelle pH monitoring in vivo and a dearth of lysosome-acidifying therapeutic agents. Here, we summarize and present evidence for the notion of defective lysosomal acidification as an early indicator of neurodegeneration and urge the critical need for technological advancement in developing tools for lysosomal pH monitoring and detection both in vivo and for clinical applications. We further discuss current preclinical pharmacological agents that modulate lysosomal acidification, including small molecules and nanomedicine, and their potential clinical translation into lysosome-targeting therapies. Both timely detection of lysosomal dysfunction and development of therapeutics that restore lysosomal function represent paradigm shifts in targeting neurodegenerative diseases.

Keywords: Alzheimer’s disease; Autophagy dysfunction; Early detection; Lysosomal de-acidification; Nanomedicine; Nanoparticles; Neurodegenerative diseases; Parkinson’s disease; Prognostic marker; Small molecules

DOI: https://doi.org/10.1186/s40035-023-00362-0

EMBO J. 2023 Jun 05. e112845

Mammalian ATG8 proteins maintain autophagosomal membrane integrity through ESCRTs.

Ruheena Javed, Ashish Jain, Thabata Duque, Emily Hendrix, Masroor Ahmad Paddar, Sajjad Khan, Aurore Claude-Taupin, Jingyue Jia, Lee Allers, Fulong Wang, Michal Mudd, Graham Timmins, Keith Lidke, Tor Erik Rusten, Prithvi Reddy Akepati, Yi He, Fulvio Reggiori, Eeva-Liisa Eskelinen, Vojo Deretic.

The canonical autophagy pathway in mammalian cells sequesters diverse cytoplasmic cargo within the double membrane autophagosomes that eventually convert into degradative compartments via fusion with endolysosomal intermediates. Here, we report that autophagosomal membranes show permeability in cells lacking principal ATG8 proteins (mATG8s) and are unable to mature into autolysosomes. Using a combination of methods including a novel in vitro assay to measure membrane sealing, we uncovered a previously unappreciated function of mATG8s to maintain autophagosomal membranes in a sealed state. The mATG8 proteins GABARAP and LC3A bind to key ESCRT-I components contributing, along with other ESCRTs, to the integrity and imperviousness of autophagic membranes. Autophagic organelles in cells lacking mATG8s are permeant, are arrested as amphisomes, and do not progress to functional autolysosomes. Thus, autophagosomal organelles need to be maintained in a sealed state in order to become lytic autolysosomes.

Keywords: ATG8; ESCRT; LC3; amphisome; autophagy

DOI: https://doi.org/10.15252/embj.2022112845