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α-Synuclein Overexpression Induces Lysosomal Dysfunction and Autophagy Impairment in Human Neuroblastoma SH-SY5Y

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Abstract

Although the etiology of Parkinson's disease (PD) is multifactorial, it has been linked to abnormal accumulation of α-synuclein (α-syn) in dopaminergic neurons, which could lead to dysfunctions on intracellular organelles, with potential neurodegeneration. Patients with familial early-onset PD frequently present mutation in the α-syn gene (SNCA), which encodes mutant α-syn forms, such as A30P and A53T, which potentially regulate Ca2+ unbalance. Here we investigated the effects of overexpression of wild-type α-syn (WT) and the mutant forms A30P and A53T, on modulation of lysosomal Ca2+ stores and further autophagy activation. We found that in α-syn-overexpressing cells, there was a decrease in Ca2+ released from endoplasmic reticulum (ER) which is related to the increase in lysosomal Ca2+ release, coupled to lysosomal pH alkalization. Interestingly, α-syn-overexpressing cells showed lower LAMP1 levels, and a disruption of lysosomal morphology and distribution, affecting autophagy. Interestingly, all these effects were more evident with A53T mutant isoform when compared to A30P and WT α-syn types, indicating that the pathogenic phenotype for PD is potentially related to impairment of α-syn degradation. Taken together, these events directly impact PD-related dysfunctions, being considered possible molecular targets for neuroprotection.

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Abbreviations

α-syn:

α-synuclein

Baf A1:

Bafilomycin-A1

CICR:

Calcium-induced calcium release

ER:

Endoplasmic reticulum

GPN:

Glycyl-l-phenylalanine 2-naphthylamide

IP3R:

Inositol 1,4,5-trisphosphate receptor

LAMP1:

Lysosomal membrane-associated protein 1

MCSs:

Membrane contact sites

NAADP:

Nicotinic acid adenine dinucleotide phosphate

PD:

Parkinson’s disease

RyR:

Ryanodine receptor

SERCA:

Sarco/endoplasmic Ca2+-ATPase

SH-SY5Y:

Human neuroblastoma cell line

SNpc:

Substantia nigra pars compacta

STV:

Starvation

TPCs:

Two-pore channels

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Acknowledgements

We thank Marina Yukari Kubota, Cícero Ramos dos Santos, Maria de Lourdes Santos, Elizabeth Kanashiro for technical assistance, and Grant Churchill for providing NAADP-AM.

Funding

This study was supported by Fundação de Amparo à Pesquisa do Estado de São Paulo—FAPESP: 2013/20073-2; 2019/02821-8 (SSS); 2017/10863-7 (GJSP); 2016/20796-2 (RPU). Conselho Nacional de Desenvolvimento Científico e Tecnológico: Universal 421603/2018-6 (GJSP); PVE 401236/2014-5 (SSS); PVE 401141/2014-4 (CB). The Master Fellowship (ACN) was supported by Coordenação de Aperfeiçoamento de Pessoal de Nível Superior—Brasil (CAPES). Confocal microscope Zeiss LSM 780, facility from the Instituto de Farmacologia e Biologia Molecular (INFAR) was supported by Financiadora de Estudos e Projetos (FINEP) and FAPESP.

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Authors and Affiliations

  1. Department of Pharmacology, Escola Paulista de Medicina, Universidade Federal de São Paulo (UNIFESP), Rua Três de Maio Street, 100, São Paulo, SP, 04044-020, Brazil

    Ana Carolina Nascimento, Adolfo G. Erustes, Patrícia Reckziegel, Claudia Bincoletto, Gustavo J. S. Pereira & Soraya S. Smaili

  2. Department of Biological Sciences, Diadema Campus, Universidade Federal de São Paulo (UNIFESP), Professor Arthur Riedel Street, Diadema, SP, 09972-270, Brazil

    Rodrigo P. Ureshino

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  1. Ana Carolina Nascimento
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  6. Gustavo J. S. Pereira
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Contributions

All authors had full access to all the data in the study and take responsibility for the integrity of the data and the accuracy of the data analysis. Study concept and design: GJSP, SSS. Acquisition of data: ACN, AGE. Analysis and interpretation of data: ACN, AGE, GJSP, PR, CB. Drafting of the manuscript: ACN, AGE, PR, CB, RPU. Critical revision of the manuscript for important intellectual content: GJSP, SSS. Statistical analysis: ACN. Study supervision: GJSP, SSS.

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Correspondence to Gustavo J. S. Pereira or Soraya S. Smaili.

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Nascimento, A.C., Erustes, A.G., Reckziegel, P. et al. α-Synuclein Overexpression Induces Lysosomal Dysfunction and Autophagy Impairment in Human Neuroblastoma SH-SY5Y. Neurochem Res 45, 2749–2761 (2020). https://doi.org/10.1007/s11064-020-03126-8

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