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Presence of Extracellular Alpha-Synuclein Aggregates Trigger Astrocytic Degeneration Through Enhanced Membrane Rigidity and Deregulation of Store-Operated Calcium Entry (SOCE) into the Endoplasmic Reticulum

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Abstract

α-Synuclein has a critical role in Parkinson’s disease, but the mechanism of how extracellular α-synuclein aggregates lead to astrocytic degeneration remains unknown. Our recent study in astrocytes highlighted that α-synuclein aggregates undergo lower endocytosis than the monomeric-form, even while displaying a higher impact on glutathione-machinery and glutamate-metabolism under sublethal conditions. As optimal intracellular calcium levels are essential for these functions, we aimed to study the effect of extracellular α-synuclein aggregates on ER calcium entry. We assessed the association of extracellular aggregated-α-synuclein (WT and A30P/A53T double-mutant) with the astrocytic membrane (lipid rafts) and studied its effects on membrane fluidity, ER stress, and ER calcium refilling in three systems—purified rat primary midbrain astrocyte culture, human iPSC-derived astrocytes, and U87 cells. The corresponding timeline effect on mitochondrial membrane potential was also evaluated. Post-24 h exposure to extracellular WT and mutant α-synuclein aggregates, fluorescence-based studies showed a significant increase in astrocyte membrane rigidity over control, with membrane association being significantly higher for the double mutant aggregates. α-Synuclein aggregates also showed preferentially higher association with lipid rafts of astrocytic membrane. A simultaneous increase in ER stress markers (phosphorylated PERK and CHOP) with significantly higher SOCE was also observed in aggregate-treated astrocytes, with higher levels for double mutant variant. These observations correlate with increased expression of SOCE markers, especially Orai3, on plasma membrane. Alterations in mitochondrial membrane potential were only noted post-48 h of exposure to α-synuclein aggregates. We therefore suggest that in astrocytes, α-synuclein-aggregates preferentially associate with lipid rafts of membrane, altering membrane fluidity and consequently inducing ER stress mediated by interaction with membrane SOCE proteins, resulting in higher Ca2+ entry. A distinct cascade of events of sequential impairment of ER followed by mitochondrial alteration is observed. The study provides novel evidence elucidating relationships between extracellular α-synuclein aggregates and organellar stress in astrocytes and indicates the therapeutic potential in targeting the association of α-synuclein aggregates with astrocytic membrane.

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All data generated or analyzed during this study are included in this published article (and its supplementary information files).

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Acknowledgements

We acknowledge the support of Vice Chancellor and Registrar of NIMHANS, Bengaluru, for extending infrastructure facilities for the present work. We acknowledge Prof. V. Ravi and Dr. Manjunath, Department of Neurovirology, NIMHANS for access to Advanced Flow Cytometer facility. We acknowledge Mr. Girish Waghmare, Junior Scientific Officer, Biophysics Department, for his skilled help in obtaining the brain slices using vibratome. We acknowledge Prof. Colin Jamora, NCBS, for his valuable scientific inputs and Prof. Ramesh Bhonde for his critical comments.

Funding

This work is supported by a grant obtained from Department of Biotechnology (DBT), Government of India, New Delhi; contract grant No. BT/PR21526/MED/122/49/2016. AR is supported by DST-INSPIRE Ph.D. fellowship. RB is supported by UGC NET-JRF.

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  1. Department of Biophysics, National Institute of Mental Health and Neurosciences, Institute of National Importance, Bengaluru, 560029, Karnataka, India

    Aishwarya Raj, Roon Banerjee & Indrani Datta

  2. Department of Neuropathology, National Institute of Mental Health and Neurosciences, Institute of National Importance, Bengaluru, 560029, Karnataka, India

    Rashmi Santhoshkumar & Chandrasekhar Sagar

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Conceptualization: I.D; methodology: I.D and A.R; formal analysis and investigation: A.R, R.B, R.S, and C.S; writing—original draft preparation: A.R; writing—review and editing: I.D; funding acquisition: I.D; resources: I.D and C.S; supervision: I.D and C.S. All authors commented on previous versions of the manuscript. All authors read and approved the final manuscript.

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Correspondence to Indrani Datta.

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Approval of Institutional Animal Ethics Committee (IAEC) of National Institute of Mental Health and Neuro Sciences (NIMHANS) was obtained for all animal experiments (IAEC reference no. AEC/70/456/B.P and AEC/70/455/B.P.). Established and previously published hiPSC line was used for this study. The hiPSC line used is already established and published previously. For the hiPSCs differentiation to astrocytes, approval was obtained from Institutional Committee for Stem Cell Research (IC-SCR) with the IC-SCR no. SEC/05/030/BP.

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Raj, A., Banerjee, R., Santhoshkumar, R. et al. Presence of Extracellular Alpha-Synuclein Aggregates Trigger Astrocytic Degeneration Through Enhanced Membrane Rigidity and Deregulation of Store-Operated Calcium Entry (SOCE) into the Endoplasmic Reticulum. Mol Neurobiol 60, 5309–5329 (2023). https://doi.org/10.1007/s12035-023-03400-0

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