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Macroautophagy, including synaptic autophagy, supports physiological synaptic pruning and plasticity, while disruption of autophagy profoundly affects neuronal development, structure, function, and survival. Neurons depend on maintaining high-quality mitochondria, and altered selective mitochondrial autophagy (mitophagy) is strongly linked to genetic and environmental causes of neurodegenerative diseases. This review summarizes advances across in vitro/in vivo models, glia, and iPSC-derived neurons, focusing on synaptic effects of disease-linked genes and highlighting diagnostic and therapeutic potentials of autophagy-related pathways.",{"@graph":69,"@context":123},[70,84,106],{"@type":71,"itemListElement":72},"BreadcrumbList",[73,77,79,82],{"item":74,"name":75,"@type":76,"position":8},"https://docshare.wps.com","Home","ListItem",{"item":78,"name":9,"@type":76,"position":14},"https://docshare.wps.com/document/",{"item":80,"name":35,"@type":76,"position":81},"https://docshare.wps.com/document/healthcare/",3,{"item":83,"name":65,"@type":76,"position":19},"https://docshare.wps.com/document/autophagy-and-mitophagy-at-the-synapse-and-beyond-implications-for-learning-memory-and-neurological-disorders/418923/",{"url":83,"name":65,"@type":85,"image":86,"author":91,"headline":65,"publisher":94,"fileFormat":97,"inLanguage":63,"description":67,"dateModified":98,"datePublished":99,"encodingFormat":97,"isAccessibleForFree":100,"interactionStatistic":101},"DigitalDocument",{"url":87,"@type":88,"width":89,"height":90},"https://docshare.wps.com/thumbnails/autophagy-and-mitophagy-at-the-synapse-and-beyond-implications-for-learning-memory-and-neurological-disorders/418923.png","ImageObject",300,407,{"name":92,"@type":93},"วิน","Person",{"url":74,"name":95,"@type":96},"DocShare","Organization","application/pdf","2026-11-07","2026-09-28",true,{"@type":102,"interactionType":103,"userInteractionCount":105},"InteractionCounter",{"@type":104},"ViewAction",13,{"@type":107,"mainEntity":108},"FAQPage",[109,115,119],{"name":110,"@type":111,"acceptedAnswer":112},"What role does autophagy play at synapses under normal conditions?","Question",{"text":113,"@type":114},"Synaptic autophagy via macroautophagy supports physiological synaptic pruning and plasticity when disease- and aging-related stressors are absent.","Answer",{"name":116,"@type":111,"acceptedAnswer":117},"Why is mitophagy particularly important for neurons?",{"text":118,"@type":114},"Neurons rely on high mitochondrial quality to sustain metabolic demands, and selective mitochondrial autophagy helps maintain that quality; disruptions are implicated in neurodegenerative and neurodevelopmental diseases.",{"name":120,"@type":111,"acceptedAnswer":121},"How does disruption of autophagy affect neurons?",{"text":122,"@type":114},"Impaired autophagy has profound effects on neuronal development, structure, function, and survival, and it can also disturb cellular quality control processes.","https://schema.org",{"og:url":83,"og:type":125,"og:title":65,"og:site_name":95,"og:description":67},"article",{"robots":127,"canonical":83},"index,follow",{"doc_id":129,"site_id":62},418923,1790719102,{"code":4,"msg":5,"data":132},{"doc_id":129,"user_id":133,"nickname":92,"user_avatar":134,"doc_module":4,"category_id":34,"category_name":35,"doc_title":65,"doc_description":67,"doc_content":135,"file_id":136,"file_url":137,"file_type":138,"file_size":139,"view_count":105,"is_deleted":4,"is_public":8,"is_downloadable":8,"audit_status":8,"page_count":140,"language":141,"language_code":63,"site_id":62,"html_lang":63,"table_of_contents":142,"faqs":143,"seo_title":144,"seo_description":67,"update_tm":145,"read_time":146,"preview_page_count":4},2336475104736,"https://ap-avatar.wpscdn.com/avatar/22000c4c5e0e5b17e70?x-image-process=image/resize,m_fixed,w_180,h_180&k=1786591360781797222","AUTOPHAGY  \n2026, VOL. 22, NO. 1, 10–52  \n[https://doi.org/10.1080/15548627.2025.2581217](https://doi.org/10.1080/15548627.2025.2581217)  \nREVIEW  \nAutophagy and mitophagy at the synapse and beyond: implications for learning, memory and neurological disorders  \nJiayi Lu a *, Damian N. Di Florio b*, Patricia Boya c, Sandra Maday d, Wolfdieter Springer b, and Charleen T. Chu a  \naDepartment of Pathology/Division of Neuropathology, University of Pittsburgh School of Medicine, Pittsburgh, PA, USA; bDepartment of Neuroscience, Mayo Clinic, Jacksonville, FL, USA; cDepartment of Neuroscience and Movement Sciences, University of Fribourg, Fribourg, Switzerland; dDepartment of Neuroscience, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA, USA  \nABSTRACT  \nThe human brain is one of the most metabolically active tissues in the body, due in large part to the activity of trillions of synaptic connections. Under normal conditions, macroautophagy/autophagy atthe synapse plays a crucial role in synaptic pruning and plasticity, which occurs physiologically in the absence of disease- or aging-related stressors. Disruption of autophagy has profound effects on neuron development, structure, function, and survival. Neurons are dependent upon maintaining high-quality mitochondria, and alterations in selective mitochondrial autophagy (mitophagy) are heavily implicated in both genetic and environmental etiologies of neurodegenerative diseases. The unique spatial and functional demands of neurons result in differences in the regulation of metabolic, autophagic, mitophagic and biosynthetic processes compared to other cell types. Here, we review recent advances in autophagy and mitophagy research with an emphasis on studies involving primary neurons in vitro and in vivo, glial cells, and iPSC-differentiated neurons. The synaptic functions of genes whose mutations implicate autophagic or mitophagic dysfunction in hereditary neurodegenerative and neurodevelopmental diseases are summarized. Finally, we discuss the diagnostic and therapeutic potentials of autophagy-related pathways.  \nAbbreviations: AD: Alzheimer disease; ALS: amyotrophic lateral sclerosis; APP: amyloid beta precursor protein; ASD: autism-spectrum disorder; BDNF: brain-derived neurotrophic factor; BPAN: β-propeller protein associated neurodegeneration; CR: caloric restriction; ΔN111: deleted N-terminal region 111 residues; DLG4/PSD95: discs large MAGUK scaffold protein 4; ER: endoplasmic reticulum; FTD: frontotemporal dementia; HD: Huntington disease; LIR: LC3-interacting region; LRRK2: leucine rich repeat kinase 2; LTD: long-term depression; LTP: long-term potentiation; MAP1LC3/LC3: microtubule associated protein 1 light chain 3; OMM: outer mitochondrial membrane; PD: Parkinson spectrum diseases; PGRN: progranulin; PINK1: PTEN induced kinase 1; PRKA/PKA: protein kinase cAMP-activated; PtdIns3P: phosphatidylinositol-3-phosphate; p-S65-Ub: ubiquitin phosphorylated at serine 65; PTM: post-translational modification; TREM2: triggering receptor expressed on myeloid cells 2  \nARTICLE HISTORY  \nReceived 2 April 2025 Revised 14 October 2025 Accepted 22 October 2025  \nKEYWORDS  \nBiomarkers; dementia; dendritic spines;  \nmitochondria;  \nneurodegenerative diseases; neurodevelopmental disorders; Parkinson disease; synaptic plasticity  \nThe neuron faces unique challenges in maintaining cellular quality over the lifetime. Although we now know that there are sites of adult neurogenesis in the human brain [ 1], the vast majority of neurons are irreplaceable, surviving on the order of 100 years in long-lived individuals. Autophagy, the process by which damaged or unneeded cellular constituents are targeted to the lysosome for degradation, plays a key role in cellular quality control, regulating differentiation, cell survival and renewal of eukaryotic cells. Given that neurons are highly dependent on mitochondrial respiration, maintaining high quality mitochondria through selective","cbCail1DPnhYD5PL","https://ap.wps.com/l/cbCail1DPnhYD5PL","pdf",1695518,43,"English","# Abstract\n# Neuronal quality control and lifespan dependence\n# Spatial and structural challenges of neurons\n# Synapse organization and mitochondrial–calcium interplay\n# Disease-linked genes and synaptic implications\n# Diagnostic and therapeutic potentials of autophagy pathways","[{\"question\":\"What role does autophagy play at synapses under normal conditions?\",\"answer\":\"Synaptic autophagy via macroautophagy supports physiological synaptic pruning and plasticity when disease- and aging-related stressors are absent.\"},{\"question\":\"Why is mitophagy particularly important for neurons?\",\"answer\":\"Neurons rely on high mitochondrial quality to sustain metabolic demands, and selective mitochondrial autophagy helps maintain that quality; disruptions are implicated in neurodegenerative and neurodevelopmental diseases.\"},{\"question\":\"How does disruption of autophagy affect neurons?\",\"answer\":\"Impaired autophagy has profound effects on neuronal development, structure, function, and survival, and it can also disturb cellular quality control processes.\"}]","Autophagy and mitophagy at the synapse and beyond - implications for learning, memory and neurological disorders | PDF",1790614911,108]