bims-proarb 2023-05-21 papers

bims-proarb

Biomed News

on Proteostasis in aging and regenerative biology

Issue of 2023‒05‒21
sixteen papers selected by
Rich Giadone
Harvard University

To aggregate or not to aggregate - Is it a matter of the ribosome?
Yeast chaperones and ubiquitin ligases contribute to proteostasis during arsenite stress by preventing or clearing protein aggregates.
Molecular Chaperones' Potential against Defective Proteostasis of Amyotrophic Lateral Sclerosis.
The Toxicity of Protein Aggregates: New Insights into the Mechanisms.
The endoplasmic reticulum stress sensor IRE1 regulates collagen secretion through the enforcement of the proteostasis factor P4HB/PDIA1 contributing to liver damage and fibrosis.
Beyond the unfolded protein response: Disclosing the role of XBP1s in Alzheimer's disease.
Rapamycin treatment increases survival, autophagy biomarkers and expression of the anti-aging klotho protein in elderly mice.
Proteostatic modulation in brain aging without associated Alzheimer's disease-and age-related neuropathological changes.
SQSTM1/P62 promotes lysophagy via formation of liquid-like condensates maintained by HSP27.
Senescence-related impairment of autophagy induces toxic intraneuronal amyloid-β accumulation in a mouse model of amyloid pathology.
A pesticide and iPSC dopaminergic neuron screen identifies and classifies Parkinson-relevant pesticides.
Soluble pathogenic tau enters brain vascular endothelial cells and drives cellular senescence and brain microvascular dysfunction in a mouse model of tauopathy.
Cold-induced longevity through proteasome boosting.
Patient-Specific iPSC-Derived Models Link Aberrant Endoplasmic Reticulum Stress Sensing and Response to Juvenile Osteochondritis Dissecans Etiology.
Distinct Signaling Pathways for Autophagy-Driven Cell Death and Survival in Adult Hippocampal Neural Stem Cells.
α-Synuclein fibril and synaptic vesicle interactions lead to vesicle destruction and increased lipid-associated fibril uptake into iPSC-derived neurons.

Bioessays. 2023 May 17. e2200230

To aggregate or not to aggregate - Is it a matter of the ribosome?

Sebastian Iben.

  Neurodegenerative syndromes present as proteinopathies - does ribosomal infidelity contribute to the protein toxicity that is the driving force for neuronal cell loss? Intracellular and extracellular protein aggregates overwhelm the clearance capacity of cells and tissues. Proteins aggregate when hydrophobic residues are exposed. Hydrophobic residues become exposed when proteins are misfolded. Protein misfolding can originate from translational errors at the ribosome. Indeed, the most error-prone process in gene expression is translation at the ribosome. Recent evidence indicates that manipulating the ribosomal accuracy impacts on the lifespan of model organisms and a reduced translational accuracy is accompanied by neurodegeneration. The first hit in aging-associated neurodegenerative disease may be the well-documented decline of cellular buffering capacity by aging. A second hit that impacts on the quality of protein synthesis could be the driving force for the observed loss of proteostasis in neurodegeneration. This hypothesis provides an explanation for the late onset of most neurodegenerative diseases.

Keywords:  aging; neurodegeneration; proteostasis; ribosome; translational fidelity

DOI:  https://doi.org/10.1002/bies.202200230
FEBS Lett. 2023 May 16.

Yeast chaperones and ubiquitin ligases contribute to proteostasis during arsenite stress by preventing or clearing protein aggregates.

Joana I Rodrigues, Emma Lorentzon, Sansan Hua, Andrew Boucher, Markus J Tamás.

Arsenite causes proteotoxicity by targeting nascent proteins for misfolding and aggregation. Here, we assessed how selected yeast chaperones and ubiquitin ligases contribute to proteostasis during arsenite stress. Loss of the ribosome-associated chaperones Zuo1, Ssz1, and Ssb1/Ssb2 reduced global translation and protein aggregation, and increased arsenite resistance. Loss of cytosolic GimC/prefoldin function led to defective aggregate clearance and arsenite sensitivity. Arsenite did not induce ribosomal stalling or impair ribosome quality control, and ribosome-associated ubiquitin ligases contributed little to proteostasis. Instead, the cytosolic ubiquitin ligase Rsp5 was important for aggregate clearance and resistance. Our study suggests that damage prevention, by decreased aggregate formation, and damage elimination, by enhanced aggregate clearance, are important protective mechanisms that maintain proteostasis during arsenite stress.

DOI: https://doi.org/10.1002/1873-3468.14638
Cells. 2023 05 02. pii: 1302. [Epub ahead of print]12(9):

Molecular Chaperones' Potential against Defective Proteostasis of Amyotrophic Lateral Sclerosis.

Sumit Kinger, Ankur Rakesh Dubey, Prashant Kumar, Yuvraj Anandrao Jagtap, Akash Choudhary, Amit Kumar, Vijay Kumar Prajapati, Rohan Dhiman, Amit Mishra.

  Amyotrophic lateral sclerosis (ALS) is a neuronal degenerative condition identified via a build-up of mutant aberrantly folded proteins. The native folding of polypeptides is mediated by molecular chaperones, preventing their pathogenic aggregation. The mutant protein expression in ALS is linked with the entrapment and depletion of chaperone capacity. The lack of a thorough understanding of chaperones' involvement in ALS pathogenesis presents a significant challenge in its treatment. Here, we review how the accumulation of the ALS-linked mutant FUS, TDP-43, SOD1, and C9orf72 proteins damage cellular homeostasis mechanisms leading to neuronal loss. Further, we discuss how the HSP70 and DNAJ family co-chaperones can act as potential targets for reducing misfolded protein accumulation in ALS. Moreover, small HSPB1 and HSPB8 chaperones can facilitate neuroprotection and prevent stress-associated misfolded protein apoptosis. Designing therapeutic strategies by pharmacologically enhancing cellular chaperone capacity to reduce mutant protein proteotoxic effects on ALS pathomechanisms can be a considerable advancement. Chaperones, apart from directly interacting with misfolded proteins for protein quality control, can also filter their toxicity by initiating strong stress-response pathways, modulating transcriptional expression profiles, and promoting anti-apoptotic functions. Overall, these properties of chaperones make them an attractive target for gaining fundamental insights into misfolded protein disorders and designing more effective therapies against ALS.

Keywords:  ALS; HSP27; HSP40; HSP70; HSPB8; chaperones

DOI:  https://doi.org/10.3390/cells12091302
Int J Mol Sci. 2023 Apr 28. pii: 7974. [Epub ahead of print]24(9):

The Toxicity of Protein Aggregates: New Insights into the Mechanisms.

Alessandra Bigi, Eva Lombardo, Roberta Cascella, Cristina Cecchi.

The aberrant aggregation of specific peptides and proteins is the common feature of a range of more than 50 human pathologies, collectively referred to as protein misfolding diseases [...].

DOI: https://doi.org/10.3390/ijms24097974
bioRxiv. 2023 May 02. pii: 2023.05.02.538835. [Epub ahead of print]

The endoplasmic reticulum stress sensor IRE1 regulates collagen secretion through the enforcement of the proteostasis factor P4HB/PDIA1 contributing to liver damage and fibrosis.

Younis Hazari, Hery Urra, Valeria A Garcia Lopez, Javier Diaz, Giovanni Tamburini, Mateus Milani, Philippe Pihan, Sylvere Durand, Fanny Aprahamia, Reese Baxter, Menghao Huang, X Charlie Dong, Helena Vihinen, Ana Batista-Gonzalez, Patricio Godoy, Alfredo Criollo, Vlad Ratziu, Fabienne Foufelle, Jan G Hengstler, Eija Jokitalo, Beatrice Bailly-Maitre, Jessica L Maiers, Lars Plate, Guido Kroemer, Claudio Hetz.

Collagen is one the most abundant proteins and the main cargo of the secretory pathway, contributing to hepatic fibrosis and cirrhosis due to excessive deposition of extracellular matrix. Here we investigated the possible contribution of the unfolded protein response, the main adaptive pathway that monitors and adjusts the protein production capacity at the endoplasmic reticulum, to collagen biogenesis and liver disease. Genetic ablation of the ER stress sensor IRE1 reduced liver damage and diminished collagen deposition in models of liver fibrosis triggered by carbon tetrachloride (CCl 4 ) administration or by high fat diet. Proteomic and transcriptomic profiling identified the prolyl 4-hydroxylase (P4HB, also known as PDIA1), which is known to be critical for collagen maturation, as a major IRE1-induced gene. Cell culture studies demonstrated that IRE1 deficiency results in collagen retention at the ER and altered secretion, a phenotype rescued by P4HB overexpression. Taken together, our results collectively establish a role of the IRE1/P4HB axis in the regulation of collagen production and its significance in the pathogenesis of various disease states.

DOI: https://doi.org/10.1101/2023.05.02.538835
Mol Ther. 2023 May 11. pii: S1525-0016(23)00246-0. [Epub ahead of print]

Beyond the unfolded protein response: Disclosing the role of XBP1s in Alzheimer's disease.

Elena Marcello.

DOI: https://doi.org/10.1016/j.ymthe.2023.04.015
Pharmacol Res Perspect. 2023 Jun;11(3): e01091

Rapamycin treatment increases survival, autophagy biomarkers and expression of the anti-aging klotho protein in elderly mice.

Kitti Szőke, Beáta Bódi, Zoltán Hendrik, Attila Czompa, Alexandra Gyöngyösi, Donald David Haines, Zoltán Papp, Árpád Tósaki, István Lekli.

  Previous investigations have demonstrated that treatment of animals with rapamycin increases levels of autophagy, which is a process by which cells degrade intracellular detritus, thus suppressing the emergence of senescent cells, whose pro-inflammatory properties, are primary drivers of age-associated physical decline. A hypothesis is tested here that rapamycin treatment of mice approaching the end of their normal lifespan exhibits increased survival, enhanced expression of autophagic proteins; and klotho protein-a biomarker of aging that affects whole organism senescence, and systemic suppression of inflammatory mediator production. Test groups of 24-month-old C57BL mice were injected intraperitoneally with either 1.5 mg/kg/week rapamycin or vehicle. All mice administered rapamycin survived the 12-week course, whereas 43% of the controls died. Relative to controls, rapamycin-treated mice experienced minor but significant weight loss; moreover, nonsignificant trends toward decreased levels of leptin, IL-6, IL-1β, TNF-α, IL-1α, and IGF-1, along with slight elevations in VEGF, MCP-1 were observed in the blood serum of rapamycin-treated mice. Rapamycin-treated mice exhibited significantly enhanced autophagy and elevated expression of klotho protein, particularly in the kidney. Rapamycin treatment also increased cardiomyocyte Ca2+ -sensitivity and enhanced the rate constant of force re-development, which may also contribute to the enhanced survival rate in elderly mice.

Keywords:  aging; autophagy; klotho; rapamycin; senolytics

DOI:  https://doi.org/10.1002/prp2.1091
Aging (Albany NY). 2023 May 13. 15

Proteostatic modulation in brain aging without associated Alzheimer's disease-and age-related neuropathological changes.

Pol Andrés-Benito, Ignacio Íñigo-Marco, Marta Brullas, Margarita Carmona, José Antonio Del Rio, Joaquín Fernández-Irigoyen, Enrique Santamaría, Mónica Povedano, Isidro Ferrer.

  AIMS: (Phospho)proteomics of old-aged subjects without cognitive or behavioral symptoms, and without AD-neuropathological changes and lacking any other neurodegenerative alteration will increase understanding about the physiological state of human brain aging without associate neurological deficits and neuropathological lesions.METHODS: (Phospho)proteomics using conventional label-free- and SWATH-MS (Sequential window acquisition of all theoretical fragment ion spectra mass spectrometry) has been assessed in the frontal cortex (FC) of individuals without NFTs, senile plaques (SPs) and age-related co-morbidities classified by age (years) in four groups; group 1 (young, 30-44); group 2 (middle-aged: MA, 45-52); group 3 (early-elderly, 64-70); and group 4 (late-elderly, 75-85).
RESULTS: Protein levels and deregulated protein phosphorylation linked to similar biological terms/functions, but involving different individual proteins, are found in FC with age. The modified expression occurs in cytoskeleton proteins, membranes, synapses, vesicles, myelin, membrane transport and ion channels, DNA and RNA metabolism, ubiquitin-proteasome-system (UPS), kinases and phosphatases, fatty acid metabolism, and mitochondria. Dysregulated phosphoproteins are associated with the cytoskeleton, including microfilaments, actin-binding proteins, intermediate filaments of neurons and glial cells, and microtubules; membrane proteins, synapses, and dense core vesicles; kinases and phosphatases; proteins linked to DNA and RNA; members of the UPS; GTPase regulation; inflammation; and lipid metabolism. Noteworthy, protein levels of large clusters of hierarchically-related protein expression levels are stable until 70. However, protein levels of components of cell membranes, vesicles and synapses, RNA modulation, and cellular structures (including tau and tubulin filaments) are markedly altered from the age of 75. Similarly, marked modifications occur in the larger phosphoprotein clusters involving cytoskeleton and neuronal structures, membrane stabilization, and kinase regulation in the late elderly.
CONCLUSIONS: Present findings may increase understanding of human brain proteostasis modifications in the elderly in the subpopulation of individuals not having AD neuropathological change and any other neurodegenerative change in any telencephalon region.

Keywords:  (phospho)proteomics; brain aging; cytoskeleton; kinases; membranes; mitochondria; proteome; synapsis

DOI:  https://doi.org/10.18632/aging.204698
Autophagy. 2023 May 16. 1-2

SQSTM1/P62 promotes lysophagy via formation of liquid-like condensates maintained by HSP27.

Elizabeth R Gallagher, Erika L F Holzbaur.

  ABBREVIATIONS: SQSTM1/p62: Sequestosome-1; HSP27: Heat shock protein 27; LLPS: liquid-liquid phase separation; iPSC: induced pluripotent stem cell; PB1: Phox and Bem1p; FRAP: fluorescence recovery after photo-bleaching; ATG: autophagy-related; ALS: amyotrophic lateral sclerosis.

Keywords:  HSP27; Lysosomes; Sqstm1/P62; lysophagy; neurodegeneration; phase separation

DOI:  https://doi.org/10.1080/15548627.2023.2210943
Acta Neuropathol Commun. 2023 May 17. 11(1): 82

Senescence-related impairment of autophagy induces toxic intraneuronal amyloid-β accumulation in a mouse model of amyloid pathology.

Nuria Suelves, Shirine Saleki, Tasha Ibrahim, Debora Palomares, Sebastiaan Moonen, Marta J Koper, Céline Vrancx, Devkee M Vadukul, Nicolas Papadopoulos, Nikenza Viceconte, Eloïse Claude, Rik Vandenberghe, Christine A F von Arnim, Stefan N Constantinescu, Dietmar Rudolf Thal, Anabelle Decottignies, Pascal Kienlen-Campard.

  Aging is the main risk factor for Alzheimer's disease (AD) and other neurodegenerative pathologies, but the molecular and cellular changes underlying pathological aging of the nervous system are poorly understood. AD pathology seems to correlate with the appearance of cells that become senescent due to the progressive accumulation of cellular insults causing DNA damage. Senescence has also been shown to reduce the autophagic flux, a mechanism involved in clearing damaged proteins from the cell, and such impairment has been linked to AD pathogenesis. In this study, we investigated the role of cellular senescence on AD pathology by crossing a mouse model of AD-like amyloid-β (Aβ) pathology (5xFAD) with a mouse model of senescence that is genetically deficient for the RNA component of the telomerase (Terc-/-). We studied changes in amyloid pathology, neurodegeneration, and the autophagy process in brain tissue samples and primary cultures derived from these mice by complementary biochemical and immunostaining approaches. Postmortem human brain samples were also processed to evaluate autophagy defects in AD patients. Our results show that accelerated senescence produces an early accumulation of intraneuronal Aβ in the subiculum and cortical layer V of 5xFAD mice. This correlates with a reduction in amyloid plaques and Aβ levels in connecting brain regions at a later disease stage. Neuronal loss was specifically observed in brain regions presenting intraneuronal Aβ and was linked to telomere attrition. Our results indicate that senescence affects intraneuronal Aβ accumulation by impairing autophagy function and that early autophagy defects can be found in the brains of AD patients. Together, these findings demonstrate the instrumental role of senescence in intraneuronal Aβ accumulation, which represents a key event in AD pathophysiology, and emphasize the correlation between the initial stages of amyloid pathology and defects in the autophagy flux.

Keywords:  Alzheimer’s disease; Autophagy; Cellular senescence; Intraneuronal Aβ; Telomere shortening

DOI:  https://doi.org/10.1186/s40478-023-01578-x
Nat Commun. 2023 May 16. 14(1): 2803

A pesticide and iPSC dopaminergic neuron screen identifies and classifies Parkinson-relevant pesticides.

Kimberly C Paul, Richard C Krolewski, Edinson Lucumi Moreno, Jack Blank, Kristina M Holton, Tim Ahfeldt, Melissa Furlong, Yu Yu, Myles Cockburn, Laura K Thompson, Alexander Kreymerman, Elisabeth M Ricci-Blair, Yu Jun Li, Heer B Patel, Richard T Lee, Jeff Bronstein, Lee L Rubin, Vikram Khurana, Beate Ritz.

Parkinson's disease (PD) is a complex neurodegenerative disease with etiology rooted in genetic vulnerability and environmental factors. Here we combine quantitative epidemiologic study of pesticide exposures and PD with toxicity screening in dopaminergic neurons derived from PD patient induced pluripotent stem cells (iPSCs) to identify Parkinson's-relevant pesticides. Agricultural records enable investigation of 288 specific pesticides and PD risk in a comprehensive, pesticide-wide association study. We associate long-term exposure to 53 pesticides with PD and identify co-exposure profiles. We then employ a live-cell imaging screening paradigm exposing dopaminergic neurons to 39 PD-associated pesticides. We find that 10 pesticides are directly toxic to these neurons. Further, we analyze pesticides typically used in combinations in cotton farming, demonstrating that co-exposures result in greater toxicity than any single pesticide. We find trifluralin is a driver of toxicity to dopaminergic neurons and leads to mitochondrial dysfunction. Our paradigm may prove useful to mechanistically dissect pesticide exposures implicated in PD risk and guide agricultural policy.

DOI: https://doi.org/10.1038/s41467-023-38215-z
Nat Commun. 2023 Apr 25. 14(1): 2367

Soluble pathogenic tau enters brain vascular endothelial cells and drives cellular senescence and brain microvascular dysfunction in a mouse model of tauopathy.

Stacy A Hussong, Andy Q Banh, Candice E Van Skike, Angela O Dorigatti, Stephen F Hernandez, Matthew J Hart, Beatriz Ferran, Haneen Makhlouf, Maria Gaczynska, Pawel A Osmulski, Salome A McAllen, Kelly T Dineley, Zoltan Ungvari, Viviana I Perez, Rakez Kayed, Veronica Galvan.

Vascular mechanisms of Alzheimer's disease (AD) may constitute a therapeutically addressable biological pathway underlying dementia. We previously demonstrated that soluble pathogenic forms of tau (tau oligomers) accumulate in brain microvasculature of AD and other tauopathies, including prominently in microvascular endothelial cells. Here we show that soluble pathogenic tau accumulates in brain microvascular endothelial cells of P301S(PS19) mice modeling tauopathy and drives AD-like brain microvascular deficits. Microvascular impairments in P301S(PS19) mice were partially negated by selective removal of pathogenic soluble tau aggregates from brain. We found that similar to trans-neuronal transmission of pathogenic forms of tau, soluble tau aggregates are internalized by brain microvascular endothelial cells in a heparin-sensitive manner and induce microtubule destabilization, block endothelial nitric oxide synthase (eNOS) activation, and potently induce endothelial cell senescence that was recapitulated in vivo in microvasculature of P301S(PS19) mice. Our studies suggest that soluble pathogenic tau aggregates mediate AD-like brain microvascular deficits in a mouse model of tauopathy, which may arise from endothelial cell senescence and eNOS dysfunction triggered by internalization of soluble tau aggregates.

DOI: https://doi.org/10.1038/s41467-023-37840-y
Nat Rev Mol Cell Biol. 2023 Apr 25.

Cold-induced longevity through proteasome boosting.

Eytan Zlotorynski.

DOI: https://doi.org/10.1038/s41580-023-00610-1
Stem Cells Transl Med. 2023 May 15. 12(5): 293-306

Patient-Specific iPSC-Derived Models Link Aberrant Endoplasmic Reticulum Stress Sensing and Response to Juvenile Osteochondritis Dissecans Etiology.

Giuliana E Salazar-Noratto, Catriana C Nations, Hazel Y Stevens, Maojia Xu, Sean Gaynard, Claire Dooley, Nica de Nijs, Katya McDonagh, Sanbing Shen, S Clifton Willimon, Frank Barry, Robert E Guldberg.

  Juvenile osteochondritis dissecans (JOCD) is a pediatric disease, which begins with an osteonecrotic lesion in the secondary ossification center which, over time, results in the separation of the necrotic fragment from the parent bone. JOCD predisposes to early-onset osteoarthritis. However, the knowledge gap in JOCD pathomechanisms severely limits current therapeutic strategies. To elucidate its etiology, we conducted a study with induced pluripotent stem cells (iPSCs) from JOCD and control patients. iPSCs from skin biopsies were differentiated to iMSCs (iPSC-derived mesenchymal stromal cells) and subjected to chondrogenic and endochondral ossification, and endoplasmic reticulum (ER)-stress induction assays. Our study, using 3 JOCD donors, showed that JOCD cells have lower chondrogenic capability and their endochondral ossification process differs from control cells; yet, JOCD- and control-cells accomplish osteogenesis of similar quality. Our findings show that endoplasmic reticulum stress sensing and response mechanisms in JOCD cells, which partially regulate chondrocyte and osteoblast differentiation, are related to these differences. We suggest that JOCD cells are more sensitive to ER stress than control cells, and in pathological microenvironments, such as microtrauma and micro-ischemia, JOCD pathogenesis pathways may be initiated. This study is the first, to the best of our knowledge, to realize the important role that resident cells and their differentiating counterparts play in JOCD and to put forth a novel etiological hypothesis that seeks to consolidate and explain previously postulated hypotheses. Furthermore, our results establish well-characterized JOCD-specific iPSC-derived in vitro models and identified potential targets which could be used to improve diagnostic tools and therapeutic strategies in JOCD.

Keywords:  articulation disorders; chondrogenesis; endoplasmic reticulum stress; induced pluripotent stem cells; osteochondritis dissecans; osteogenesis

DOI:  https://doi.org/10.1093/stcltm/szad018
Int J Mol Sci. 2023 May 05. pii: 8289. [Epub ahead of print]24(9):

Distinct Signaling Pathways for Autophagy-Driven Cell Death and Survival in Adult Hippocampal Neural Stem Cells.

Seol-Hwa Jeong, Hyun-Kyu An, Shinwon Ha, Seong-Woon Yu.

  Autophagy is a cellular catabolic process that degrades and recycles cellular materials. Autophagy is considered to be beneficial to the cell and organism by preventing the accumulation of toxic protein aggregates, removing damaged organelles, and providing bioenergetic substrates that are necessary for survival. However, autophagy can also cause cell death depending on cellular contexts. Yet, little is known about the signaling pathways that differentially regulate the opposite outcomes of autophagy. We have previously reported that insulin withdrawal (IW) or corticosterone (CORT) induces autophagic cell death (ACD) in adult hippocampal neural stem (HCN) cells. On the other hand, metabolic stresses caused by 2-deoxy-D-glucose (2DG) and glucose-low (GL) induce autophagy without death in HCN cells. Rather, we found that 2DG-induced autophagy was cytoprotective. By comparing IW and CORT conditions with 2DG treatment, we revealed that ERK and JNK are involved with 2DG-induced protective autophagy, whereas GSK-3β regulates death-inducing autophagy. These data suggest that cell death and survival-promoting autophagy undergo differential regulation with distinct signaling pathways in HCN cells.

Keywords:  ERK; GSK-3β; JNK; adult hippocampal neural stem cells; autophagic cell death; autophagy

DOI:  https://doi.org/10.3390/ijms24098289
Commun Biol. 2023 May 15. 6(1): 526

α-Synuclein fibril and synaptic vesicle interactions lead to vesicle destruction and increased lipid-associated fibril uptake into iPSC-derived neurons.

Amberley D Stephens, Ana Fernandez Villegas, Chyi Wei Chung, Oliver Vanderpoorten, Dorothea Pinotsi, Ioanna Mela, Edward Ward, Thomas M McCoy, Robert Cubitt, Alexander F Routh, Clemens F Kaminski, Gabriele S Kaminski Schierle.

Monomeric alpha-synuclein (aSyn) is a well characterised protein that importantly binds to lipids. aSyn monomers assemble into amyloid fibrils which are localised to lipids and organelles in insoluble structures found in Parkinson's disease patient's brains. Previous work to address pathological aSyn-lipid interactions has focused on using synthetic lipid membranes, which lack the complexity of physiological lipid membranes. Here, we use physiological membranes in the form of synaptic vesicles (SV) isolated from rodent brain to demonstrate that lipid-associated aSyn fibrils are more easily taken up into iPSC-derived cortical i3Neurons. Lipid-associated aSyn fibril characterisation reveals that SV lipids are an integrated part of the fibrils and while their fibril morphology differs from aSyn fibrils alone, the core fibril structure remains the same, suggesting the lipids lead to the increase in fibril uptake. Furthermore, SV enhance the aggregation rate of aSyn, yet increasing the SV:aSyn ratio causes a reduction in aggregation propensity. We finally show that aSyn fibrils disintegrate SV, whereas aSyn monomers cause clustering of SV using small angle neutron scattering and high-resolution imaging. Disease burden on neurons may be impacted by an increased uptake of lipid-associated aSyn which could enhance stress and pathology, which in turn may have fatal consequences for neurons.

DOI: https://doi.org/10.1038/s42003-023-04884-1