The spread of prion-like proteins by lysosomes and tunneling nanotubes: Implications for neurodegenerative diseases

Progression of pathology in neurodegenerative diseases is hypothesized to be a non–cell-autonomous process that may be mediated by the productive spreading of prion-like protein aggregates from a “donor cell” that is the source of misfolded aggregates to an “acceptor cell” in which misfolding is propagated by conversion of the normal protein. Although the proteins involved in the various diseases are unrelated, common pathways appear to be used for their intercellular propagation and spreading. Here, we summarize recent evidence of the molecular mechanisms relevant for the intercellular trafficking of protein aggregates involved in prion, Alzheimer’s, Huntington’s, and Parkinson’s diseases. We focus in particular on the common roles that lysosomes and tunneling nanotubes play in the formation and spreading of prion-like assemblies.

• Publication year

  2017

• Venue

  Journal of Cell Biology

• Publication date

  2017-09-04

• Fields of study

  Biology, Medicine

• Identifiers
  DOI 10.1083/jcb.201701047PMID 28724527PMCID 5584166
• External record

  Open on Semantic Scholar

• Source metadata

  Semantic Scholar, PubMed

• No claims are published for this paper.

• No concepts are published for this paper.

• The Role of Oxidative Stress

  2018cited by this paper
• Prion-like mechanisms and potential therapeutic targets in neurodegenerative disorders.

  2017cited by this paper
• Mechanochemical Signaling Directs Cell-Shape Change.

  2017cited by this paper
• Visualization of prion-like transfer in Huntington's disease models.

  2017cited by this paper
• α-Synuclein transfer between neurons and astrocytes indicates that astrocytes play a role in degradation rather than in spreading

  2017cited by this paper
• The role of extracellular vesicles in neurodegenerative diseases.

  2017cited by this paper
• Neuronal activity enhances tau propagation and tau pathology in vivo

  2016cited by this paper
• Differential identity of Filopodia and Tunneling Nanotubes revealed by the opposite functions of actin regulatory complexes

  2016cited by this paper
• Axonal transport and secretion of fibrillar forms of α-synuclein, Aβ42 peptide and HTTExon 1

  2016cited by this paper
• Prions and Protein Assemblies that Convey Biological Information in Health and Disease.

  2016cited by this paper
• Accumulation of amyloid-β by astrocytes result in enlarged endosomes and microvesicle-induced apoptosis of neurons

  2016cited by this paper
• The missing link: does tunnelling nanotube-based supercellularity provide a new understanding of chronic and lifestyle diseases?

  2016influential reference
• The Cellular Phase of Alzheimer's Disease.

  2016cited by this paper
• The Autophagy-Lysosomal Pathway in Neurodegeneration: A TFEB Perspective.

  2016cited by this paper
• The lysosome as a command-and-control center for cellular metabolism

  2016cited by this paper
• Astrocyte-to-neuron intercellular prion transfer is mediated by cell-cell contact

  2016cited by this paper
• Structural Variation in Amyloid-β Fibrils from Alzheimer’s Disease Clinical Subtypes

  2016cited by this paper
• Defects in trafficking bridge Parkinson's disease pathology and genetics

  2016cited by this paper
• The activities of amyloids from a structural perspective

  2016influential reference
• Tunneling nanotubes spread fibrillar α‐synuclein by intercellular trafficking of lysosomes

  2016cited by this paper
• A neuroprotective role for microglia in prion diseases

  2016cited by this paper
• Sorting out release, uptake and processing of alpha‐synuclein during prion‐like spread of pathology

  2016cited by this paper
• TDP-43 or FUS-induced misfolded human wild-type SOD1 can propagate intercellularly in a prion-like fashion

  2016cited by this paper
• Restricted Location of PSEN2/γ-Secretase Determines Substrate Specificity and Generates an Intracellular Aβ Pool.

  2016cited by this paper
• Tunneling nanotubes: A possible highway in the spreading of tau and other prion-like proteins in neurodegenerative diseases

  2016cited by this paper
• Impact of lysosome status on extracellular vesicle content and release.

  2016cited by this paper
• Cell Biology of Prions and Prionoids: A Status Report.

  2016cited by this paper
• Brain Disorders Due to Lysosomal Dysfunction.

  2016cited by this paper
• Trafficking and degradation pathways in pathogenic conversion of prions and prion-like proteins in neurodegenerative diseases.

  2015cited by this paper
• Loss of glucocerebrosidase 1 activity causes lysosomal dysfunction and α-synuclein aggregation

  2015cited by this paper
• Early etiology of Alzheimer’s disease: tipping the balance toward autophagy or endosomal dysfunction?

  2015cited by this paper
• TDP-43 is intercellularly transmitted across axon terminals

  2015cited by this paper
• ESCRTs regulate amyloid precursor protein sorting in multivesicular bodies and intracellular amyloid-β accumulation

  2015cited by this paper
• Retromer in Alzheimer disease, Parkinson disease and other neurological disorders

  2015influential reference
• Transfer of mitochondria via tunneling nanotubes rescues apoptotic PC12 cells

  2015cited by this paper
• Brief Reports: Lysosomal Cross‐Correction by Hematopoietic Stem Cell‐Derived Macrophages Via Tunneling Nanotubes

  2015cited by this paper
• Exosomes: Mechanisms of Uptake

  2015cited by this paper
• Prion strains are differentially released through the exosomal pathway

  2015cited by this paper
• Prion-like transmission of neuronal huntingtin aggregates to phagocytic glia in the Drosophila brain

  2015cited by this paper
• Removing endogenous tau does not prevent tau propagation yet reduces its neurotoxicity

  2015cited by this paper
• Exposure to ALS-FTD-CSF generates TDP-43 aggregates in glioblastoma cells through exosomes and TNTs-like structure

  2015cited by this paper
• Lysosomal calcium signaling regulates autophagy via calcineurin and TFEB

  2015cited by this paper
• The Role of Oxidative Stress in Neurodegenerative Diseases

  2015cited by this paper
• Prion aggregates transfer through tunneling nanotubes in endocytic vesicles

  2015influential reference
• Synaptic Contacts Enhance Cell-to-Cell Tau Pathology Propagation.

  2015cited by this paper
• Faculty Opinions recommendation of Lysosomal calcium signalling regulates autophagy through calcineurin and TFEB.

  2015cited by this paper
• Transcellular spreading of huntingtin aggregates in the Drosophila brain

  2015cited by this paper
• Toxic species in amyloid disorders: Oligomers or mature fibrils

  2015cited by this paper
• Axonal and Transynaptic Spread of Prions

  2014cited by this paper
• Intercellular transfer of tau aggregates and spreading of tau pathology: Implications for therapeutic strategies.

  2014cited by this paper
• Alpha‐synuclein transfers from neurons to oligodendrocytes

  2014cited by this paper
• Translation of the Prion Protein mRNA Is Robust in Astrocytes but Does Not Amplify during Reactive Astrocytosis in the Mouse Brain

  2014cited by this paper
• Transneuronal propagation of mutant huntingtin contributes to non–cell autonomous pathology in neurons

  2014cited by this paper
• Biogenesis, secretion, and intercellular interactions of exosomes and other extracellular vesicles.

  2014cited by this paper
• Cell-to-cell transmission of pathogenic proteins in neurodegenerative diseases

  2014cited by this paper
• Spreading of amyloid-β peptides via neuritic cell-to-cell transfer is dependent on insufficient cellular clearance.

  2014cited by this paper
• Highly Infectious CJD Particles Lack Prion Protein but Contain Many Viral‐Linked Peptides by LC‐MS/MS

  2014cited by this paper
• Mutation in VPS35 associated with Parkinson’s disease impairs WASH complex association and inhibits autophagy

  2014influential reference
• Enhancing Astrocytic Lysosome Biogenesis Facilitates Aβ Clearance and Attenuates Amyloid Plaque Pathogenesis

  2014cited by this paper
• Selective clearance of aberrant tau proteins and rescue of neurotoxicity by transcription factor EB

  2014cited by this paper
• Oral Treatment Targeting the Unfolded Protein Response Prevents Neurodegeneration and Clinical Disease in Prion-Infected Mice

  2013cited by this paper
• Phosphatidylinositol-3-phosphate regulates sorting and processing of amyloid precursor protein through the endosomal system

  2013cited by this paper
• Myo10 is a key regulator of TNT formation in neuronal cells

  2013cited by this paper
• Glucocerebrosidase inhibition causes mitochondrial dysfunction and free radical damage

  2013cited by this paper
• Signals from the lysosome: a control centre for cellular clearance and energy metabolism

  2013cited by this paper
• Alpha-Synuclein Induces Lysosomal Rupture and Cathepsin Dependent Reactive Oxygen Species Following Endocytosis

  2013influential reference
• Transfer of polyglutamine aggregates in neuronal cells occurs in tunneling nanotubes

  2013cited by this paper
• Biology and genetics of prions causing neurodegeneration.

  2013influential reference
• Physiological release of endogenous tau is stimulated by neuronal activity

  2013cited by this paper
• Lysosomal NEU1 deficiency affects Amyloid Precursor Protein levels and amyloid-β secretion via deregulated lysosomal exocytosis

  2013cited by this paper
• TFEB-mediated autophagy rescues midbrain dopamine neurons from α-synuclein toxicity

  2013cited by this paper
• Autophagic failure promotes the exocytosis and intercellular transfer of α-synuclein

  2013cited by this paper
• The cell biology of prion-like spread of protein aggregates: mechanisms and implication in neurodegeneration.

  2013cited by this paper
• Autophagy is involved in oligodendroglial precursor-mediated clearance of amyloid peptide

  2013cited by this paper
• Neuron‐to‐neuron transmission of α‐synuclein fibrils through axonal transport

  2012cited by this paper
• Fibrillar α-synuclein and huntingtin exon 1 assemblies are toxic to the cells.

  2012cited by this paper
• The retromer complex – endosomal protein recycling and beyond

  2012cited by this paper
• Prion-like spread of protein aggregates in neurodegeneration

  2012cited by this paper
• Constitutive secretion of tau protein by an unconventional mechanism.

  2012cited by this paper
• Intracerebral inoculation of pathological α-synuclein initiates a rapidly progressive neurodegenerative α-synucleinopathy in mice

  2012cited by this paper
• The role of the cofilin-actin rod stress response in neurodegenerative diseases uncovers potential new drug targets

  2012influential reference
• Trans-cellular Propagation of Tau Aggregation by Fibrillar Species*

  2012cited by this paper
• Prion‐infected cells regulate the release of exosomes with distinct ultrastructural features

  2012cited by this paper
• A lysosome-to-nucleus signalling mechanism senses and regulates the lysosome via mTOR and TFEB

  2012cited by this paper
• PGC-1α Rescues Huntington’s Disease Proteotoxicity by Preventing Oxidative Stress and Promoting TFEB Function

  2012cited by this paper
• MTORC1 functions as a transcriptional regulator of autophagy by preventing nuclear transport of TFEB

  2012cited by this paper
• Pathological α-Synuclein Transmission Initiates Parkinson-like Neurodegeneration in Nontransgenic Mice

  2012cited by this paper
• Amyloid precursor protein (APP) traffics from the cell surface via endosomes for amyloid β (Aβ) production in the trans-Golgi network

  2012cited by this paper
• Small Misfolded Tau Species Are Internalized via Bulk Endocytosis and Anterogradely and Retrogradely Transported in Neurons*

  2012cited by this paper
• Wiring through tunneling nanotubes – from electrical signals to organelle transfer

  2012cited by this paper
• Exosomal cell-to-cell transmission of alpha synuclein oligomers

  2012cited by this paper
• Endogenous prion protein conversion is required for prion‐induced neuritic alterations and neuronal death

  2012cited by this paper
• Alpha-Synuclein Cell-to-Cell Transfer and Seeding in Grafted Dopaminergic Neurons In Vivo

  2012cited by this paper
• Spreading of Neurodegenerative Pathology via Neuron-to-Neuron Transmission of β-Amyloid

  2012cited by this paper
• Trans-Synaptic Spread of Tau Pathology In Vivo

  2012cited by this paper
• Prion protein and its conformational conversion: a structural perspective.

  2011cited by this paper
• Tunneling-nanotube development in astrocytes depends on p53 activation

  2011cited by this paper
• Lysosomal dysfunction increases exosome-mediated alpha-synuclein release and transmission

  2011cited by this paper
• Prion propagation and toxicity in vivo occur in two distinct mechanistic phases

  2011cited by this paper
• S3‐03‐05: Transmission and Spreading of Tauopathy in Transgenic Mouse Brain

  2011cited by this paper

• Fluorogenic Rhodamine Probes Enable High-Resolution Visualization of Plasma Membrane Nanostructures.

  2026cites this paper
• Tunneling nanotubes induced by pseudorabies virus facilitate viral transmission in neuronal cells to evade the immune system.

  2026cites this paper
• Targeted tau protein degradation: a promising therapeutic approach for tauopathies.

  2025cites this paper
• Intercellular communication in the brain through a dendritic nanotubular network.

  2025cites this paper
• Harnessing nanotechnology for stem-cell therapies: revolutionizing neurodegenerative disorder treatments – a state-of-the-art update

  2025cites this paper
• Intercellular transfer of proteins and mitochondria - the contribution of proteomics.

  2025cites this paper
• Lysosomal Enhancement Prevents Infection with PrPSc, α-Synuclein & Tau Prions

  2025cites this paper
• Beyond synapses: cytoplasmic connections in brain function and evolution

  2025cites this paper
• Protrusion‐Derived Extracellular Vesicles (PD‐EVs) and Their Diverse Origins: Key Players in Cellular Communication, Cancer Progression, and T Cell Modulation

  2025cites this paper
• Intercellular communication in the brain via dendritic nanotubular network

  2025cites this paper
• Transforming the concept of connectivity: unveiling tunneling nanotube biology, and their roles in brain development and neurodegeneration.

  2025cites this paper
• Lipid metabolism, remodelling and intercellular transfer in the CNS

  2025cites this paper
• Scutellarin ameliorates ischemia/reperfusion-mediated endothelial dysfunction by upregulating cathepsin D expression to rescue autophagy-lysosomal function

  2025cites this paper
• Enhanced lysosomal activity prevents infection with PrPSc and the seeding activity of α-synuclein & tau prions

  2025cites this paper
• Proteomic landscape of tunneling nanotubes reveals CD9 and CD81 tetraspanins as key regulators

  2024cites this paper
• The role of the proteosurfaceome and exoproteome in bacterial coaggregation.

  2024cites this paper
• Tunneling Nanotubes: The Cables for Viral Spread and Beyond.

  2024cites this paper
• Intercellular Highways in Transport Processes.

  2024cites this paper
• Intercellular Communication Through Microtubular Highways.

  2024cites this paper
• Astroglia proliferate upon the biogenesis of tunneling nanotubes via α-synuclein dependent transient nuclear translocation of focal adhesion kinase

  2024influential citation
• Tunneling Nanotubes: The Transport Highway for Astrocyte-Neuron Communication in the Central Nervous System.

  2024cites this paper
• Astroglia proliferate upon biogenesis of tunneling nanotubes and clearance of α-synuclein toxicities

  2023influential citation
• Reducing huntingtin by immunotherapy delays disease progression in a mouse model of Huntington disease.

  2023cites this paper
• The direct transfer approach for transcellular drug delivery

  2023cites this paper
• Tunneling nanotubes: The intercellular conduits contributing to cancer pathogenesis and its therapy.

  2023cites this paper
• Actin-based protrusions at a glance.

  2023cites this paper
• Tau accumulation in degradative organelles is associated to lysosomal stress

  2023cites this paper
• Aggregation, Transmission, and Toxicity of the Microtubule-Associated Protein Tau: A Complex Comprehension

  2023cites this paper
• Tunneling Nanotube: An Enticing Cell–Cell Communication in the Nervous System

  2023cites this paper
• Rehabilitation for non-motor symptoms for patients with Parkinson's disease from an α-synuclein perspective: a narrative review.

  2023cites this paper
• Editorial: Synergistic interactions between exosomes and tunneling nanotubes in long-range intercellular transfer

  2023cites this paper
• Maintenance of cathepsin D-dependent autophagy-lysosomal function protects against cardiac ischemia/reperfusion injury.

  2023cites this paper
• Hijacking intercellular trafficking for the spread of protein aggregates in neurodegenerative diseases: a focus on tunneling nanotubes (TNTs)

  2023cites this paper
• Tunneling Nanotubes: A New Target for Nanomedicine?

  2022cites this paper
• Proteinopathies: Deciphering Physiology and Mechanisms to Develop Effective Therapies for Neurodegenerative Diseases

  2022cites this paper
• Membrane interaction to intercellular spread of pathology in Alzheimer’s disease

  2022influential citation
• Hunting for the cause: Evidence for prion-like mechanisms in Huntington’s disease

  2022cites this paper
• Tunneling nanotubes provide a route for SARS-CoV-2 spreading

  2022cites this paper
• Tunneling Nanotubes Facilitate Intercellular Protein Transfer and Cell Networks Function

  2022cites this paper
• SARS-CoV-2: A Master of Immune Evasion

  2022cites this paper
• Prionoids in amyotrophic lateral sclerosis

  2022cites this paper
• Protective effect of the tunneling nanotube-TNFAIP2/M-sec system on podocyte autophagy in diabetic nephropathy

  2022cites this paper
• C9ORF72-derived poly-GA DPRs undergo endocytic uptake in iAstrocytes and spread to motor neurons

  2022cites this paper
• Tunneling nanotubes and mesenchymal stem cells: New insights into the role of melatonin in neuronal recovery

  2022cites this paper
• Recombinant pro-CTSD (cathepsin D) enhances SNCA/α-Synuclein degradation in α-Synucleinopathy models

  2022cites this paper
• Exosomal RNAs in diagnosis and therapies

  2022cites this paper
• Metabolic tricks of cancer cells.

  2022cites this paper
• An arrayed genome‐wide perturbation screen identifies the ribonucleoprotein Hnrnpk as rate‐limiting for prion propagation

  2022cites this paper
• Tunneling nanotubes: Reshaping connectivity.

  2021cites this paper
• Rational design of a lysosome-targeting and near-infrared absorbing Ru(II)-BODIPY conjugate for photodynamic therapy.

  2021cites this paper
• Role of the Endolysosomal Pathway and Exosome Release in Tau Propagation.

  2021cites this paper
• Peering into tunneling nanotubes—The path forward

  2021influential citation
• Tunneling Nanotubes: A Novel Pharmacological Target for Neurodegenerative Diseases?

  2021cites this paper
• Protective Role of the M-Sec–Tunneling Nanotube System in Podocytes

  2021cites this paper
• The potential role of glial cells in driving the prion-like transcellular propagation of tau in tauopathies

  2021cites this paper
• Impact of α-Synuclein Fibrillar Strains and β-Amyloid Assemblies on Mouse Cortical Neurons Endo-Lysosomal Logistics

  2021cites this paper
• Birbirinden uzak endotel hücreleri arasında nanotüp tünellemenin görüntülenmesi

  2021cites this paper
• Phagocytic Glial Cells in Brain Homeostasis

  2021cites this paper
• α-Synuclein fibrils subvert lysosome structure and function for the propagation of protein misfolding between cells through tunneling nanotubes

  2021cites this paper
• Amyloid-β induced membrane damage instigates tunneling nanotube-like conduits by p21-activated kinase dependent actin remodulation.

  2021cites this paper
• Photoreceptor nanotubes mediate the in vivo exchange of intracellular material

  2021cites this paper
• Intercellular Propagation and Aggregate Seeding of Mutant Ataxin-1

  2021cites this paper
• A lateral protrusion latticework connects neuroepithelial cells and is regulated during neurogenesis

  2021cites this paper
• Maintenance and loss of endocytic organelle integrity: mechanisms and implications for antigen cross-presentation

  2021cites this paper
• Alpha-synuclein spreading mechanisms in Parkinson's disease: The role of membrane receptors

  2021cites this paper
• 1 1 2 3 A lateral protrusion latticework connects neuroepithelial cells and is 4 regulated during neurogenesis

  2021cites this paper
• Tunneling nanotubes provide a novel route for SARS-CoV-2 spreading between permissive cells and to non-permissive neuronal cells

  2021cites this paper
• Oxidative stress and Rho GTPases in the biogenesis of tunnelling nanotubes: implications in disease and therapy

  2021cites this paper
• Molecular events underlying the cell‐to‐cell transmission of α‐synuclein

  2020cites this paper
• Role of tau protein in Alzheimer's disease: The prime pathological player.

  2020cites this paper
• The Role of Vesicle Trafficking Defects in the Pathogenesis of Prion and Prion-Like Disorders

  2020cites this paper
• Protrusion-Mediated Signaling Regulates Patterning of the Developing Nervous System

  2020cites this paper
• Molecular Chaperones: A Double-Edged Sword in Neurodegenerative Diseases

  2020influential citation
• Rab35 and its effectors promote formation of tunneling nanotubes in neuronal cells

  2020cites this paper
• The NSs Protein Encoded by the Virulent Strain of Rift Valley Fever Virus Targets the Expression of Abl2 and the Actin Cytoskeleton of the Host, Affecting Cell Mobility, Cell Shape, and Cell-Cell Adhesion

  2020cites this paper
• Fate and propagation of endogenously formed Tau aggregates in neuronal cells

  2020cites this paper
• Patient-derived glioblastoma stem cells transfer mitochondria through tunneling nanotubes in tumor organoids

  2020cites this paper
• The Ways of Actin: Why Tunneling Nanotubes Are Unique Cell Protrusions.

  2020cites this paper
• RNA transfer through tunneling nanotubes.

  2020cites this paper
• Tunneling Nanotubes: The Fuel of Tumor Progression?

  2020cites this paper
• The actin cytoskeletal network plays a role in yeast prion transmission and contributes to prion stability

  2020cites this paper
• Alzheimer’s disease progression characterized by alterations in the molecular profiles and biogenesis of brain extracellular vesicles

  2020cites this paper
• Tunneling Nanotubes and the Eye: Intercellular Communication and Implications for Ocular Health and Disease

  2020cites this paper
• Amyloid-β induced membrane damage instigates tunneling nanotubes by exploiting PAK1 dependent actin remodulation

  2020cites this paper
• Neurodegenerative disease-associated protein aggregates are poor inducers of the heat shock response in neuronal-like cells

  2020cites this paper
• Bridging the Gap: Virus Long-Distance Spread via Tunneling Nanotubes

  2020cites this paper
• Fine intercellular connections in development: TNTs, cytonemes, or intercellular bridges?

  2020cites this paper
• Neurodegenerative disease-associated protein aggregates are poor inducers of the heat shock response in neuronal cells

  2020cites this paper
• Highly efficient intercellular spreading of protein misfolding mediated by viral ligand-receptor interactions

  2020cites this paper
• The prion-like spreading of α-synuclein: From in vitro to in vivo models of Parkinson's disease.

  2019cites this paper
• Cell-autonomous and non-cell autonomous protection of DNAJB6 in Huntington’s disease

  2019cites this paper
• Identification d'un profil de marqueurs périphériques lié aux scores cognitifs dans le plasma et les vésicules extracellulaires durant le développement de la maladie d'Alzheimer: évolution de marqueurs liés au stress oxydatif et aux mécanismes physiopathologiques.

  2019cites this paper
• Neuronal Soma-Derived Degradative Lysosomes Are Continuously Delivered to Distal Axons to Maintain Local Degradation Capacity

  2019cites this paper
• Amyloid-β induced membrane damage instigates tunnelling nanotubes and direct cell- 1 to-cell transfer 2

  2019cites this paper
• Prion-like properties of assembled TDP-43.

  2019cites this paper
• Seeding Activity-Based Detection Uncovers the Different Release Mechanisms of Seed-Competent Tau Versus Inert Tau via Lysosomal Exocytosis

  2019cites this paper
• Mechanisms of secretion and spreading of pathological tau protein

  2019cites this paper
• The Wnt/Ca2+ pathway is involved in interneuronal communication mediated by tunneling nanotubes

  2019cites this paper
• Molecular mechanisms of proteinopathies across neurodegenerative disease: a review

  2019cites this paper
• Progress in the Genetic Analysis of Parkinson's Disease.

  2019cites this paper