Photoreceptors are highly polarized sensory neurons. Precise localization of signaling molecules within the ciliary outer segment is critical for photoreceptor function and viability. The small GTPase Arl3 plays a particularly important role in photoreceptors as it regulates outer segment enrichment of lipidated proteins essential for the visual response: transducin-α, transducin-γ, PDEα, PDE β, and Grk1. Recently, mutations in Arl3 have been identified in human patients with nonsyndromic autosomal recessive and dominant inherited retinal degenerations as well as syndromic Joubert syndrome including retinal dystrophy.
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- - Mitochondria are crucial for the health and functioning of retinal cells, and problems with mitochondria are linked to various retinal degenerative diseases, particularly in cases involving mutations.
- - This study focused on how specific mutations related to ARL3 affect mitochondrial function in fibroblast cells from patients with ARL3-related rod-cone dystrophy, revealing decreased mitochondrial respiration and increased harmful reactive oxygen species (ROS).
- - Comparative testing in another cell type (ARPE-19) indicated that ARL3 mutations lead to both decreased mitochondrial function and increased apoptosis, highlighting the complex relationship between these mutations and mitochondrial health.
Mechanisms underlying morphological and functional changes of cilia in fibroblasts derived from patients bearing ARL3 and ARL3 mutations.
FASEB J
March 2024
Henan Eye Institute, Henan Eye Hospital, People's Hospital of Zhengzhou University, Henan Provincial People's Hospital, Zhengzhou, Henan, China.
ARL3 is essential for cilia development, and mutations in ARL3 are closely associated with ciliopathies. In a previous study, we observed distinct phenotypes of retinal dystrophy in patients with heterozygous ARL3 and compound heterozygous ARL3 mutations, indicating that different mutation types may exert diverse effects on their functions. Here, we generated transformed immortal fibroblast cells from patients carrying heterozygous ARL3 and compound heterozygous ARL3 mutations, and systematically evaluated their cilia morphology and function, which were further validated in ARPE-19 cells.
View Article and Find Full Text PDFRABL2 promotes the outward transition zone passage of signaling proteins in cilia via ARL3.
Proc Natl Acad Sci U S A
August 2023
State Key Laboratory of Food Nutrition and Safety, Institute of Health Biotechnology, Tianjin University of Science and Technology, Tianjin 300457, China.
Certain transmembrane and membrane-tethered signaling proteins export from cilia as BBSome cargoes via the outward BBSome transition zone (TZ) diffusion pathway, indispensable for maintaining their ciliary dynamics to enable cells to sense and transduce extracellular stimuli inside the cell. Murine Rab-like 2 (Rabl2) GTPase resembles Arf-like 3 (ARL3) GTPase in promoting outward TZ passage of the signaling protein cargo-laden BBSome. During this process, ARL3 binds to and recruits the retrograde IFT train-dissociated BBSome as its effector to diffuse through the TZ for ciliary retrieval, while how RABL2 and ARL3 cross talk in this event remains uncertain.
View Article and Find Full Text PDFHuman Mutations in Arl3, a Small GTPase Involved in Lipidated Cargo Delivery to the Cilia, Cause Retinal Dystrophy.
Adv Exp Med Biol
July 2023
Department of Ophthalmology and Visual Science, University of Michigan, Ann Arbor, MI, USA.
Photoreceptors are highly polarized sensory neurons. Precise localization of signaling molecules within the ciliary outer segment is critical for photoreceptor function and viability. The small GTPase Arl3 plays a particularly important role in photoreceptors as it regulates outer segment enrichment of lipidated proteins essential for the visual response: transducin-α, transducin-γ, PDEα, PDE β, and Grk1.
View Article and Find Full Text PDFNon-syndromic Retinal Degeneration Caused by Pathogenic Variants in Joubert Syndrome Genes.
Adv Exp Med Biol
July 2023
Ocular Genomics Institute, Massachusetts Eye and Ear, Department of Ophthalmology, Harvard Medical School, Boston, MA, USA.
Inherited retinal degenerations (IRDs) are a group of genetic disorders characterized by progressive dysfunction and loss of photoreceptors. IRDs are classified as non-syndromic or syndromic, depending on whether retinal degeneration manifests alone or in combination with other associated symptoms. Joubert syndrome (JBTS) is a genetically and clinically heterogeneous disorder affecting the central nervous system and other organs and tissues, including the neuroretina.
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