ArticleNeuron2024
Rapid iPSC inclusionopathy models shed light on formation, consequence, and molecular subtype of α-synuclein inclusions.
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Article in Neuron, 2024. The graph could read no effect estimate from its abstract, so it casts no vote on the map. An erratum has been issued. Cited by 24 papers.
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24 citing papers in PubMed.
- Cellular and systemic modifiers of alpha-synuclein proteostasis.Philosophical transactions of the Royal Society of London. Series B, Biological sciences · 2026Review
- Beyond phenotypic markers: rethinking dopaminergic identity in iPSC-derived neurons.Cell communication and signaling : CCS · 2026Review
- Cholesterol dysregulation in APOE4 astrocytes promotes α-synuclein pathology in miBrains.Cell stem cell · 2026Article
- Quantifying the Acute Toxicity of Alpha-Synuclein Membrane-Accumulation in a Cell-Based Assay.Journal of molecular neuroscience : MN · 2026Article
- Sex-aware causal inference assessment of the immune system in complex neurodegenerative diseases.Brain : a journal of neurology · 2026Article
- Modeling Parkinson's pathology in human iPSC dopaminergic neurons uncovers key mechanisms of Lewy body formation and heterogeneity.Science advances · 2026Article
- NERINE reveals rare variant associations in gene networks across phenotypes and implicates an SNCA-PRL-LRRK2 subnetwork in Parkinson's disease.Cell genomics · 2026Article
- Ultrastructural diversity and subcellular organization of nigral Lewy pathology in Parkinson's disease.Nature communications · 2026Article
- WDR44 drives de novo α-synuclein aggregation at the lysosomal membrane and promotes neuronal dysfunction in Parkinson's Disease.bioRxiv : the preprint server for biology · 2026Article
- Cytotoxic T cell recognition of α-synuclein drives pathogenic immune responses in multiple system atrophy.Proceedings of the National Academy of Sciences of the United States of America · 2026Article
- Cracking the code of native amyloid fibrils: advances and next steps to enable pathology-informed therapeutic and diagnostic.Nature structural & molecular biology · 2026Review
- Development of convolutional neural networks for automated brain-wide histopathological analysis in mouse models of synucleinopathies.NPJ Parkinson's disease · 2025Article
- Lipid nanoparticle formulation for gene editing and RNA-based therapies for glioblastoma.Neuro-oncology · 2025Article
- Correlative light and electron microscopy for human brain and other biological models.Nature protocols · 2025Review
- Alpha-synuclein abundance and localization are regulated by the RNA-binding protein PUMILIO1.Cell reports · 2025Article
- The potential of brain organoids in addressing the heterogeneity of synucleinopathies.Cellular and molecular life sciences : CMLS · 2025Review
- A personalised and comprehensive approach is required to suppress or replenish SNCA for Parkinson's disease.NPJ Parkinson's disease · 2025Review
- Cholesterol-mediated Lysosomal Dysfunction inbioRxiv : the preprint server for biology · 2025Article
- Parkinson disease-associated toxic exposures selectively up-regulate vesicular glutamate transporter vGlut2 in a model of human cortical neurons.Molecular biology of the cell · 2025Article
- Design principles to tailor Hsp104 therapeutics.Cell reports · 2024Article
Corrections and comments
- Erratum issued
Authors and funding
54 authors.
Isabel LamAnn Romney Center for Neurologic Diseases, Brigham and Women's Hospital, Boston, MA, USA; Division of Movement Disorders, American Parkinson Disease Association (APDA) Center for Advanced Research and MSA Center of Excellence, Department of Neurology, Brigham and Women's Hospital, Boston, MA, USA; Harvard Medical School, Boston, MA, USA.
Alain NdayisabaAnn Romney Center for Neurologic Diseases, Brigham and Women's Hospital, Boston, MA, USA; Division of Movement Disorders, American Parkinson Disease Association (APDA) Center for Advanced Research and MSA Center of Excellence, Department of Neurology, Brigham and Women's Hospital, Boston, MA, USA; Harvard Medical School, Boston, MA, USA; Division of Neurobiology, Department of Neurology, Medical University of Innsbruck, Innsbruck, Austria.
Amanda J LewisÉcole Polytechnique Fédérale de Lausanne and University of Lausanne, Lausanne, Switzerland.
YuHong FuThe University of Sydney Brain and Mind Centre and Faculty of Medicine and Health School of Medical Science, Sydney, NSW, Australia.
Giselle T SagredoThe University of Sydney Brain and Mind Centre and Faculty of Medicine and Health School of Medical Science, Sydney, NSW, Australia.
Anastasia KuzkinaAnn Romney Center for Neurologic Diseases, Brigham and Women's Hospital, Boston, MA, USA; Division of Movement Disorders, American Parkinson Disease Association (APDA) Center for Advanced Research and MSA Center of Excellence, Department of Neurology, Brigham and Women's Hospital, Boston, MA, USA; Harvard Medical School, Boston, MA, USA.
Ludovica ZaccagniniDementia Research Institute, University College London, London, UK.
Meral CelikagDementia Research Institute, University College London, London, UK.
Jackson SandoeWhitehead Institute for Biomedical Research, Cambridge, MA, USA.
Ricardo L SanzAnn Romney Center for Neurologic Diseases, Brigham and Women's Hospital, Boston, MA, USA; Division of Movement Disorders, American Parkinson Disease Association (APDA) Center for Advanced Research and MSA Center of Excellence, Department of Neurology, Brigham and Women's Hospital, Boston, MA, USA; Harvard Medical School, Boston, MA, USA.
Aazam VahdatshoarAnn Romney Center for Neurologic Diseases, Brigham and Women's Hospital, Boston, MA, USA; Division of Movement Disorders, American Parkinson Disease Association (APDA) Center for Advanced Research and MSA Center of Excellence, Department of Neurology, Brigham and Women's Hospital, Boston, MA, USA.
Timothy D MartinHarvard Medical School, Boston, MA, USA; Division of Genetics, Department of Medicine, Brigham and Women's Hospital, Boston, MA, USA; Howard Hughes Medical Institute, Chevy Chase, MD, USA.
Nader MorshedHarvard Medical School, Boston, MA, USA; Howard Hughes Medical Institute, Chevy Chase, MD, USA; Boston Children's Hospital, Boston, MA, USA; The Broad Institute of MIT and Harvard, Cambridge, MA, USA.
Toru IchihashiNikon Corporation, Tokyo, Japan.
Arati TripathiAnn Romney Center for Neurologic Diseases, Brigham and Women's Hospital, Boston, MA, USA; Harvard Medical School, Boston, MA, USA.
Nagendran RamalingamAnn Romney Center for Neurologic Diseases, Brigham and Women's Hospital, Boston, MA, USA; Harvard Medical School, Boston, MA, USA.
Charlotte Oettgen-SuazoAnn Romney Center for Neurologic Diseases, Brigham and Women's Hospital, Boston, MA, USA; Division of Movement Disorders, American Parkinson Disease Association (APDA) Center for Advanced Research and MSA Center of Excellence, Department of Neurology, Brigham and Women's Hospital, Boston, MA, USA.
Theresa BartelsWhitehead Institute for Biomedical Research, Cambridge, MA, USA.
Manel BoussoufAnn Romney Center for Neurologic Diseases, Brigham and Women's Hospital, Boston, MA, USA; Division of Movement Disorders, American Parkinson Disease Association (APDA) Center for Advanced Research and MSA Center of Excellence, Department of Neurology, Brigham and Women's Hospital, Boston, MA, USA.
Max SchäbingerAnn Romney Center for Neurologic Diseases, Brigham and Women's Hospital, Boston, MA, USA; Division of Movement Disorders, American Parkinson Disease Association (APDA) Center for Advanced Research and MSA Center of Excellence, Department of Neurology, Brigham and Women's Hospital, Boston, MA, USA.
Erinc HallacliAnn Romney Center for Neurologic Diseases, Brigham and Women's Hospital, Boston, MA, USA; Division of Movement Disorders, American Parkinson Disease Association (APDA) Center for Advanced Research and MSA Center of Excellence, Department of Neurology, Brigham and Women's Hospital, Boston, MA, USA; Harvard Medical School, Boston, MA, USA.
Xin JiangYumanity Therapeutics, Cambridge, MA, USA.
Amrita VermaAnn Romney Center for Neurologic Diseases, Brigham and Women's Hospital, Boston, MA, USA; Division of Movement Disorders, American Parkinson Disease Association (APDA) Center for Advanced Research and MSA Center of Excellence, Department of Neurology, Brigham and Women's Hospital, Boston, MA, USA.
Challana TeaUniversity of California, San Diego, San Diego, CA, USA.
Zichen WangUniversity of California, San Diego, San Diego, CA, USA.
Hiroyuki HakozakiUniversity of California, San Diego, San Diego, CA, USA.
Xiao YuAnn Romney Center for Neurologic Diseases, Brigham and Women's Hospital, Boston, MA, USA; Division of Movement Disorders, American Parkinson Disease Association (APDA) Center for Advanced Research and MSA Center of Excellence, Department of Neurology, Brigham and Women's Hospital, Boston, MA, USA.
Kelly HylesAnn Romney Center for Neurologic Diseases, Brigham and Women's Hospital, Boston, MA, USA; Division of Movement Disorders, American Parkinson Disease Association (APDA) Center for Advanced Research and MSA Center of Excellence, Department of Neurology, Brigham and Women's Hospital, Boston, MA, USA.
Chansaem ParkAnn Romney Center for Neurologic Diseases, Brigham and Women's Hospital, Boston, MA, USA; Division of Movement Disorders, American Parkinson Disease Association (APDA) Center for Advanced Research and MSA Center of Excellence, Department of Neurology, Brigham and Women's Hospital, Boston, MA, USA.
Xinyuan WangAnn Romney Center for Neurologic Diseases, Brigham and Women's Hospital, Boston, MA, USA; Division of Movement Disorders, American Parkinson Disease Association (APDA) Center for Advanced Research and MSA Center of Excellence, Department of Neurology, Brigham and Women's Hospital, Boston, MA, USA; Harvard Medical School, Boston, MA, USA.
Thorold W TheunissenWhitehead Institute for Biomedical Research, Cambridge, MA, USA.
Haoyi WangWhitehead Institute for Biomedical Research, Cambridge, MA, USA.
Rudolf JaenischWhitehead Institute for Biomedical Research, Cambridge, MA, USA.
Susan LindquistWhitehead Institute for Biomedical Research, Cambridge, MA, USA; Howard Hughes Medical Institute, Chevy Chase, MD, USA.
Beth StevensHarvard Medical School, Boston, MA, USA; Howard Hughes Medical Institute, Chevy Chase, MD, USA; Boston Children's Hospital, Boston, MA, USA; The Broad Institute of MIT and Harvard, Cambridge, MA, USA.
Nadia StefanovaDivision of Neurobiology, Department of Neurology, Medical University of Innsbruck, Innsbruck, Austria.
Gregor WenningDivision of Neurobiology, Department of Neurology, Medical University of Innsbruck, Innsbruck, Austria.
Wilma D J van de BergAmsterdam University Medical Center, Vrije Universiteit, Amsterdam, the Netherlands.
Kelvin C LukUniversity of Pennsylvania Perelman School of Medicine, Philadelphia, PA, USA.
Rosario Sanchez-PernauteBioBizkaia Health Research Institute, Barakaldo, Spain; Ikerbasque, Basque Foundation for Science, Bilbao, Spain.
Juan Carlos Gómez-EstebanBioBizkaia Health Research Institute, Barakaldo, Spain.
Daniel FelskyCentre for Addiction and Mental Health, Toronto, ON, Canada; University of Toronto, Toronto, ON, Canada.
Yasujiro KiyotaNikon Corporation, Tokyo, Japan.
Nidhi SahniThe University of Texas MD Anderson Cancer Center, Houston, TX, USA; Baylor College of Medicine, Houston, TX, USA.
S Stephen YiThe University of Texas at Austin, Austin, TX, USA.
Chee Yeun ChungYumanity Therapeutics, Cambridge, MA, USA.
Henning StahlbergÉcole Polytechnique Fédérale de Lausanne and University of Lausanne, Lausanne, Switzerland.
Isidro FerrerThe University of Barcelona, Institut d'Investigacio Biomedica de Bellvitge IDIBELL, Hospitalet de Llobregat, Barcelona, Spain.
Johannes SchönebergUniversity of California, San Diego, San Diego, CA, USA.
Stephen J ElledgeHarvard Medical School, Boston, MA, USA; Division of Genetics, Department of Medicine, Brigham and Women's Hospital, Boston, MA, USA; Howard Hughes Medical Institute, Chevy Chase, MD, USA.
Ulf DettmerAnn Romney Center for Neurologic Diseases, Brigham and Women's Hospital, Boston, MA, USA; Harvard Medical School, Boston, MA, USA.
Glenda M HallidayThe University of Sydney Brain and Mind Centre and Faculty of Medicine and Health School of Medical Science, Sydney, NSW, Australia; Aligning Science Across Parkinson's (ASAP) Collaborative Research Network, Chevy Chase, MD, USA.
Tim BartelsDementia Research Institute, University College London, London, UK.
Vikram KhuranaAnn Romney Center for Neurologic Diseases, Brigham and Women's Hospital, Boston, MA, USA; Division of Movement Disorders, American Parkinson Disease Association (APDA) Center for Advanced Research and MSA Center of Excellence, Department of Neurology, Brigham and Women's Hospital, Boston, MA, USA; Harvard Medical School, Boston, MA, USA; The Broad Institute of MIT and Harvard, Cambridge, MA, USA; Aligning Science Across Parkinson's (ASAP) Collaborative Research Network, Chevy Chase, MD, USA; Harvard Stem Cell Institute, Cambridge, MA, USA. Electronic address: khuranalab_admin@bwh.harvard.edu.
Funding
Elucidating the Biological Differences Between Distinct Fibrillar and Non-Fibrillar Alpha-Synuclein Inclusions in Human Stem-Cell ModelsR01NS109209 · NINDS · BRIGHAM AND WOMEN'S HOSPITAL · PI KHURANA, VIKRAM · 2020 to 2024
$4.5MUC San Diego Genetics Training ProgramT32GM145427 · NIGMS · UNIVERSITY OF CALIFORNIA, SAN DIEGO · PI BRUCE A HAMILTON · 2022 to 2026
$2.6MNetwork-based Framework to Decode Novel Gain-of-Function Mutations and their Mechanistic Roles in General Human DiseasesR35GM133658 · NIGMS · UNIVERSITY OF TEXAS AT AUSTIN · PI S. Stephen Yi · 2019 to 2026
$2.6MHow Serine-129 Phosphorylation Status Affects the Spreading of α-Synuclein Pathology in Vivo: a Study in Knock-in AnimalsRF1NS133979 · NINDS · BRIGHAM AND WOMEN'S HOSPITAL · PI DETTMER, ULF, RAMALINGAM, NAGENDRAN · 2023 to 2023
$2.2MPolo-like-kinase-2-dependent α-Synuclein Serine-129 Phosphorylation: a Physiological RoleDuring Synaptic ActivityRF1NS122880 · NINDS · BRIGHAM AND WOMEN'S HOSPITAL · PI DETTMER, ULF, RAMALINGAM, NAGENDRAN · 2022 to 2022
$2.1MStabilizing native α-synuclein homeostasis to prevent insoluble α-synuclein aggregatesR01NS099328 · NINDS · BRIGHAM AND WOMEN'S HOSPITAL · PI DETTMER, ULF · 2017 to 2021
$1.9MDeciphering Functional Consequences of Specific and Combinatorial Mutations in Protein Interaction NetworksR35GM137836 · NIGMS · UNIVERSITY OF TX MD ANDERSON CAN CTR · PI SAHNI, NIDHI · 2020 to 2023
$1.8MPolo-like-kinase-2-dependent α-Synuclein Serine-129 Phosphorylation: a Physiological RoleDuring Synaptic ActivityR01NS122880 · NINDS · BRIGHAM AND WOMEN'S HOSPITAL · PI Ulf Dettmer, Nagendran Ramalingam · 2025 to 2026
$1.4MContrasting pathomechanisms of membrane versus cytosol alpha-synuclein excessR21NS121826 · NINDS · BRIGHAM AND WOMEN'S HOSPITAL · PI DETTMER, ULF · 2021 to 2021
$505kDistinguishing α-Synuclein S129 Phosphorylation in Health and Lewy Body DementiaR21AG085401 · NIA · UNIVERSITY OF SOUTH FLORIDA · PI Nagendran Ramalingam · 2024 to 2026
$433kMolecular impact of endolysosomal dysfunction on neuron-glia communication pathwaysF32AG079666 · NIA · BOSTON CHILDREN'S HOSPITAL · PI MORSHED, NADER FRANCIS · 2022 to 2025
$164kNIA NIH HHS F32 AG079666NIA NIH HHS R21 AG085401NIGMS NIH HHS R35 GM133658NIGMS NIH HHS R35 GM137836NIGMS NIH HHS T32 GM145427NINDS NIH HHS R01 NS099328NINDS NIH HHS R01 NS109209NINDS NIH HHS R01 NS122880NINDS NIH HHS R21 NS121826NINDS NIH HHS RF1 NS122880NINDS NIH HHS RF1 NS133979
Abstract
The heterogeneity of protein-rich inclusions and its significance in neurodegeneration is poorly understood. Standard patient-derived iPSC models develop inclusions neither reproducibly nor in a reasonable time frame. Here, we developed screenable iPSC "inclusionopathy" models utilizing piggyBac or targeted transgenes to rapidly induce CNS cells that express aggregation-prone proteins at brain-like levels. Inclusions and their effects on cell survival were trackable at single-inclusion resolution. Exemplar cortical neuron α-synuclein inclusionopathy models were engineered through transgenic expression of α-synuclein mutant forms or exogenous seeding with fibrils. We identified multiple inclusion classes, including neuroprotective p62-positive inclusions versus dynamic and neurotoxic lipid-rich inclusions, both identified in patient brains. Fusion events between these inclusion subtypes altered neuronal survival. Proteome-scale α-synuclein genetic- and physical-interaction screens pinpointed candidate RNA-processing and actin-cytoskeleton-modulator proteins like RhoA whose sequestration into inclusions could enhance toxicity. These tractable CNS models should prove useful in functional genomic analysis and drug development for proteinopathies.
Indexed as
alpha-SynucleinInclusion BodiesInduced Pluripotent Stem CellsBrainHumansNeuronsSynucleinopathiesalpha-Synucleinactin cytoskeletonaggregationCRISPR screendementia with Lewy bodiesgliainclusioniPSCLewy bodylipidneurodegenerationneuronp62Parkinson’s diseasepiggyBacproximity labelingRab proteinRhoAsynucleinopathyubiquitinα-synuclein
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