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Exosome Release Is Modulated by the Mitochondrial-Lysosomal Crosstalk in Parkinson’s Disease Stress Conditions

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Abstract

Parkinson’s disease (PD) is a neurodegenerative disorder characterized by the progressive loss of dopaminergic neurons in the substantia nigra (SN) pars compacta region of the brain. The main pathological hallmark involves cytoplasmic inclusions of α-synuclein and mitochondrial dysfunction, which is observed in other part of the central nervous system other than SN suggesting the spread of pathogenesis to bystander neurons. The inter-neuronal communication through exosomes may play an important role in the spread of the disease; however, the mechanisms are not well elucidated. Mitochondria and its role in inter-organellar crosstalk with multivesicular body (MVB) and lysosome and its role in modulation of exosome release in PD is not well understood. In the current study, we investigated the mitochondria-lysosome crosstalk modulating the exosome release in neuronal and glial cells. We observed that PD stress showed enhanced release of exosomes in dopaminergic neurons and glial cells. The PD stress condition in these cells showed fragmented network and mitochondrial dysfunction which further leads to functional deficit of lysosomes and hence inhibition of autophagy flux. Neuronal and glial cells treated with rapamycin showed enhanced autophagy and inhibited the exosomal release. The results here suggest that maintenance of mitochondrial function is important for the lysosomal function and hence exosomal release which is important for the pathogenesis of PD.

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Acknowledgements

Authors acknowledge the DBT-MSUB-ILSPARE programme of the Department of Biochemistry, the M S University of Baroda sponsored by DBT, Government of India. Authors also acknowledge the FIST programme supported by DST, Government of India. This work is a part of the Ph.D. thesis of Fatema Currim. Fatema Currim received Junior Research Fellowship from DST-INSPIRE, Government of India. Dhruv Gohel received Senior Research Fellowship from the Indian Council of Medical Research (ICMR), Government of India. Minal Mane received Senior Research fellowship from the Council of Scientific and Industrial Research (CSIR), Government of India.

Funding

The current research work was financially supported by the Department of Biotechnology, Government of India grant (BT/PR19937/MED/122/17/2016) to RS.

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Authors and Affiliations

  1. Department of Biochemistry, Faculty of Science, The MS University of Baroda, Vadodara, Gujarat, 390002, India

    Fatema Currim, Jyoti Singh, Anjali Shinde, Dhruv Gohel, Milton Roy, Shatakshi Shukla, Minal Mane, Hitesh Vasiyani & Rajesh Singh

  2. Department of Cell and Developmental Biology, University College London, Gower Street, London, WC1E 6BT, UK

    Kritarth Singh

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  1. Fatema Currim
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Fatema Currim: Investigation, validation, writing—original draft

Jyoti Singh Anjali Shinde, Milton Roy, Dhruv Gohel, Kritarth Singh, Shatakshi Shukla, Minal Mane and Hitesh Vasiyani: Formal data analysis, methodology and resources

Rajesh Singh: Conceptualization, methodology, resources, writing—original draft, visualization, supervision and funding acquisition

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Correspondence to Rajesh Singh.

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Currim, F., Singh, J., Shinde, A. et al. Exosome Release Is Modulated by the Mitochondrial-Lysosomal Crosstalk in Parkinson’s Disease Stress Conditions. Mol Neurobiol 58, 1819–1833 (2021). https://doi.org/10.1007/s12035-020-02243-3

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