Optogenetic manipulation of lysosomal physiology and autophagy-dependent clearance of amyloid beta.

1. PLoS Biol. 2024 Apr 23;22(4):e3002591. doi: 10.1371/journal.pbio.3002591. eCollection 2024 Apr.

Optogenetic manipulation of lysosomal physiology and autophagy-dependent clearance of amyloid beta.

Zeng W(1), Li C(1)(2), Wu R(3)(4), Yang X(1), Wang Q(1), Lin B(1), Wei Y(1), Li H(1), Shan G(3)(4), Qu L(1), Cang C(1)(2)(4)(5).

Author information: (1)Institute on Aging and Brain Disorders, The First Affiliated Hospital of USTC, Division of Life Sciences and Medicine, University of Science and Technology of China, Hefei, Anhui, China. (2)Institute of Health and Medicine, Hefei Comprehensive National Science Center, Hefei, Anhui, China. (3)Department of Laboratory Medicine, The First Affiliated Hospital of USTC, Division of Life Science and Medicine, University of Science and Technology of China, Hefei, Anhui, China. (4)The CAS Key Laboratory of Innate Immunity and Chronic Disease, School of Basic Medical Sciences, Division of Life Sciences and Medicine, University of Science and Technology of China, Hefei, Anhui, China. (5)Neurodegenerative Disorder Research Center, University of Science and Technology of China, Hefei, Anhui, China.

Lysosomes are degradation centers of cells and intracellular hubs of signal transduction, nutrient sensing, and autophagy regulation. Dysfunction of lysosomes contributes to a variety of diseases, such as lysosomal storage diseases (LSDs) and neurodegeneration, but the mechanisms are not well understood. Altering lysosomal activity and examining its impact on the occurrence and development of disease is an important strategy for studying lysosome-related diseases. However, methods to dynamically regulate lysosomal function in living cells or animals are still lacking. Here, we constructed lysosome-localized optogenetic actuators, named lyso-NpHR3.0, lyso-ArchT, and lyso-ChR2, to achieve optogenetic manipulation of lysosomes. These new actuators enable light-dependent control of lysosomal membrane potential, pH, hydr