<> "The repository administrator has not yet configured an RDF license."^^ . <> . . "Human presynaptic active zone: basic biology and disease"^^ . "Presynaptic terminals release neurotransmitter in response to incoming electrical impulses, control \r\ninformation transfer between neurons in neural networks, and mediate directly or indirectly most brain \r\nfunctions. In humans, dysfunction of presynaptic terminals contributes to devastating brain disorders \r\nsuch as Alzheimer, schizophrenia, and autism. However, despite of its obvious significance, how \r\ndefects in the function of presynaptic terminals contribute to the etiology of brain disorders, remains \r\nlargely unknown. This is because not even the most fundamental operation principles of normal human \r\nnerve terminals are well-understood, let alone their dysfunction in disease. \r\nHere, I study the basic biology of human presynaptic terminals, as well as their dysregulation in \r\nautism-spectrum disorder (ASD). I focus on a protein family called RIMs (Rab interacting molecules), \r\nwhich are central components of the presynaptic active zones. I capitalized on emerging human \r\npluripotent stem-cell technologies to generate human neurons, on CRISPR/Cas9 genome editing to \r\ngenetically engineer human neurons and create disease models, and on advanced physiological and \r\nmicroscopy technologies to uncover the basic biology of human presynaptic terminals as well as their \r\ndysfunction in ASD. Remarkably, I found that compound genetic removal of both RIM1 and RIM2, the \r\nmain brain RIM isoforms, disassembles human active zones (AZ), prevents synaptic vesicle docking \r\nand priming, and blocks synaptic vesicle fusion, rendering human presynaptic terminals functionally \r\nsilent. Genetic experiments in which either RIM1 or RIM2 are selectively deleted, revealed that RIM1 \r\nis the functionally dominant isoform in human neurons. \r\nAs RIM1 is also a common target of mutations in autistic patients, I generated a panel of knock-in \r\nlines comprising all currently described ASD-linked mutations in RIM1, and analyzed systematically \r\ntheir impact on human neuron structure and function. I found that all these disease-linked variants \r\ndysregulated human synaptic communication via two convergent mechanisms: impairing either \r\nvesicle priming or calcium channel coupling to synaptic vesicles. Importantly, this translates into \r\nenhanced or reduced information flow across neural human networks, highlighting the critical role of \r\nbalanced neurotransmission in the pathogenesis of neuropsychiatric disorders. \r\nMy work offers a unifying view on the basic biology of human active zones and their dysregulation in \r\nautism. To the best of my knowledge, this study represents the first effort aiming to understand how \r\nnormal human presynaptic terminals work, and how brain disease affects them. Along this line, here I \r\ncontribute to future efforts aiming to the development of new therapeutic strategies to reverse common \r\npresynaptic mechanisms disrupted in autistic patients."^^ . "2025" . . . . . . . "Joaquín Damián Joacaz"^^ . "Campos Muñoz"^^ . "Joaquín Damián Joacaz Campos Muñoz"^^ . . . . . . "Human presynaptic active zone: basic biology and disease (PDF)"^^ . . . "Human presynaptic active zone, basic biology and disease.pdf"^^ . . . "Human presynaptic active zone: basic biology and disease (Other)"^^ . . . . . . "lightbox.jpg"^^ . . . "Human presynaptic active zone: basic biology and disease (Other)"^^ . . . . . . "preview.jpg"^^ . . . "Human presynaptic active zone: basic biology and disease (Other)"^^ . . . . . . "medium.jpg"^^ . . . "Human presynaptic active zone: basic biology and disease (Other)"^^ . . . . . . "small.jpg"^^ . . . "Human presynaptic active zone: basic biology and disease (Other)"^^ . . . . . . "indexcodes.txt"^^ . . "HTML Summary of #36792 \n\nHuman presynaptic active zone: basic biology and disease\n\n" . "text/html" . . . "500 Naturwissenschaften und Mathematik"@de . "500 Natural sciences and mathematics"@en . . . "570 Biowissenschaften, Biologie"@de . "570 Life sciences"@en . . . "610 Medizin"@de . "610 Medical sciences Medicine"@en . .