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Mechanistic Insights of Astrocyte-Mediated Hyperactive Autophagy and Loss of Motor Neuron Function in SOD1L39R Linked Amyotrophic Lateral Sclerosis

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Abstract

Amyotrophic lateral sclerosis (ALS) is a fatal neurodegenerative disorder with no cure. The reports showed the role of nearby astrocytes around the motor neurons as one among the causes of the disease. However, the exact mechanistic insights are not explored so far. Thus, in the present investigations, we employed the induced pluripotent stem cells (iPSCs) of Cu/Zn-SOD1L39R linked ALS patient to convert them into the motor neurons (MNs) and astrocytes. We report that the higher expression of stress granule (SG) marker protein G3BP1, and its co-localization with the mutated Cu/Zn-SOD1L39R protein in patient’s MNs and astrocytes are linked with AIF1-mediated upregulation of caspase 3/7 and hyper activated autophagy. We also observe the astrocyte-mediated non-cell autonomous neurotoxicity on MNs in ALS. The secretome of the patient’s iPSC-derived astrocytes exerts significant oxidative stress in MNs. The findings suggest the hyperactive status of autophagy in MNs, as witnessed by the co-distribution of LAMP1, P62 and LC3 I/II with the autolysosomes. Conversely, the secretome of normal astrocytes has shown neuroprotection in patient’s iPSC-derived MNs. The whole-cell patch-clamp assay confirms our findings at a physiological functional level in MNs. Perhaps for the first time, we are reporting that the MN degeneration in ALS triggered by the hyper-activation of autophagy and induced apoptosis in both cell-autonomous and non-cell autonomous conditions.

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Acknowledgements

Authors are thankful to Dr. Patricia S. Kuriki for preparing lenti-viral particles and flowcytometric estimation at IBUSP, Brazil, and Mr. Puneet Khare for flowcytometric experiments at CSIR-IITR, Lucknow India. The technical assistance of Mr. Waldir Caldeira, IBUSP, Brazil, is acknowledged for operation of confocal microscopy. We thank to Dr. Manisha Mishra, CSIR-IITR, India, for helping in analysis of sequencing data and Dr. Naila Lourenço, IBUSP, Brazil, for assisting in the analysis of MLPA data. We also thank Mr. Thiago Giove Mitsugi, IBUSP, Brazil, for his technical support. The financial support from Department of Biotechnology, Ministry of Science & Technology, Government of India and CNPq-Brazil (Proc. No. 405243/2015-4) through Indo-Brazil project No. DBT/IC-2/Indo-Brazil/2016-19/02 are acknowledged. This study was also partly funded by FAPESP-CEPID (2013/08028-1), CNPq (307611/2018-3), INCT-CETGEN (573633/2008-8), and FINEP-CTC (0108057900). H.U. acknowledges grant support by the São Paulo Research Foundation (FAPESP project number.2012/50880-4). A.C. was supported by a postdoctoral fellowship from FAPESP (project number 2013/02293). OKO was a visiting scholar at HCCTD-HIAE.

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Authors and Affiliations

  1. System Toxicology & Health Risk assessment Group, CSIR-Indian Institute of Toxicology Research (CSIR-IITR), Vishvigyan Bhavan, 31, Mahatma Gandhi Marg, Lucknow, Uttar Pradesh, 226001, India

    Chetan Singh Rajpurohit, Uzair Ahmad Ansari, Vinay Kumar Khanna & Aditya Bhushan Pant

  2. Academy of Scientific and Innovative Research (AcSIR), Ghaziabad, 201002, India

    Chetan Singh Rajpurohit, Uzair Ahmad Ansari, Vinay Kumar Khanna & Aditya Bhushan Pant

  3. Department of Genetics and Evolutionary Biology, Human Genome and Stem-Cell Research Center, Institute of Biosciences, University of São Paulo, São Paulo, Brazil

    Vivek Kumar, Danyllo Oliveira, Oswaldo Keith Okamoto & Mayana Zatz

  4. Department of Biochemistry, Institute of Chemistry, University of São Paulo, São Paulo, Brazil

    Arquimedes Cheffer & Henning Ulrich

  5. Institute of Reconstructive Neurobiology, University of Bonn School of Medicine & University Hospital Bonn, Bonn, Germany

    Arquimedes Cheffer

  6. Hemotherapy and Cell Therapy Department, Hospital Israelita Albert Einstein, Sao Paulo, Brazil

    Oswaldo Keith Okamoto

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  1. Chetan Singh Rajpurohit
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  2. Vivek Kumar
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  4. Danyllo Oliveira
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  8. Uzair Ahmad Ansari
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Contributions

C.S.R. and A.B.P. designed the study. C.S.R. and V.K. performed the experiments on differentiating human iPSCs into motor neurons and astrocytes. M.Z. provided ALS patient’s fibroblasts and their clinical information. D.O. designed the experiments on iPSC reprogramming of the ALS patient’s fibroblasts. A.C. designed and performed the experiments on electrophysiology under the supervision of H.U., O.K.O. supervised the research activity and experiments at IBUSP, Brazil. C.S.R., V.K.K. and A.B.P. analysed the data.

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Correspondence to Aditya Bhushan Pant.

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Rajpurohit, C.S., Kumar, V., Cheffer, A. et al. Mechanistic Insights of Astrocyte-Mediated Hyperactive Autophagy and Loss of Motor Neuron Function in SOD1L39R Linked Amyotrophic Lateral Sclerosis. Mol Neurobiol 57, 4117–4133 (2020). https://doi.org/10.1007/s12035-020-02006-0

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