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

Author(s)

Nascimento, Ana Carolina ; Erustes, Adolfo G. ; Reckziegel, Patricia ; Bincoletto, Claudia ; Ureshino, Rodrigo P. ; Pereira, Gustavo J. S. ; Smaili, Soraya S.

• Document type: Journal article
• Source: Neurochemical Research; v. 45, n. 11, p. 13-pg., 2020-09-11.

Abstract

Although the etiology of Parkinson's disease (PD) is multifactorial, it has been linked to abnormal accumulation of alpha-synuclein (alpha-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 alpha-syn gene (SNCA), which encodes mutant alpha-syn forms, such as A30P and A53T, which potentially regulate Ca(2+)unbalance. Here we investigated the effects of overexpression of wild-type alpha-syn (WT) and the mutant forms A30P and A53T, on modulation of lysosomal Ca(2+)stores and further autophagy activation. We found that in alpha-syn-overexpressing cells, there was a decrease in Ca(2+)released from endoplasmic reticulum (ER) which is related to the increase in lysosomal Ca(2+)release, coupled to lysosomal pH alkalization. Interestingly, alpha-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 alpha-syn types, indicating that the pathogenic phenotype for PD is potentially related to impairment of alpha-syn degradation. Taken together, these events directly impact PD-related dysfunctions, being considered possible molecular targets for neuroprotection. (AU)

• FAPESP's process: 13/20073-2 - Autophagy as a protective mechanism in senescent rats
• Grantee: Soraya Soubhi Smaili
• Support Opportunities: Regular Research Grants
• FAPESP's process: 19/02821-8 - Autophagy modulation by cannabinoids: neuroprotection in Parkinson's Disease
• Grantee: Soraya Soubhi Smaili
• Support Opportunities: Research Projects - Thematic Grants
• FAPESP's process: 17/10863-7 - Study of lipophagy mediated by two-pore channels receptors
• Grantee: Gustavo José da Silva Pereira
• Support Opportunities: Regular Research Grants
• FAPESP's process: 16/20796-2 - Study of estrogen receptors mediated autophagy against tau toxicity in cell and zebrafish models
• Grantee: Rodrigo Portes Ureshino
• Support Opportunities: Research Grants - Young Investigators Grants