Absence of Gem1 (mammalian Miro/Rhot) mitigates alpha-synuclein toxicity in a yeast model of Parkinson's disease

Author(s)

Melo, Thaiany Q. ; Palma, Flavio R. ; Gomes, Fernando ; Netto, Luis E. S. ; Ferrari, Merari F. R.

• Document type: Journal article
• Source: Molecular and Cellular Neuroscience; v. 122, p. 9-pg., 2022-09-01.

Abstract

Alpha-synuclein aggregation is a hallmark of Parkinson's disease (PD). Mutants A30P and A53T alpha-synuclein are known to exacerbate the toxicity of alpha-synuclein, which includes oxidative stress, mitochondrial and endoplasmic reticulum (ER) dysfunction. Saccharomyces cerevisiae (budding yeast) is a cellular model widely used to investigate mechanisms underlying neurodegenerative disorders, such as PD. In yeast, Gem1 (Miro/Rhot mammalian orthologue) coordinates mitochondrial dynamics and ER homeostasis, which is impaired in the presence of mutant alpha-synuclein and can lead to cell death. In this study, A30P or A53T alpha-synuclein were expressed in wild type or Delta Gem (deletion of Gem1 gene) yeast strains. Delta Gem cells presented decreased viability and increased mitochondrial H2O2 production and ER stress compared to wild type cells. However, in the presence of mutant alpha-synuclein, Delta Gem cells showed increased growth compared to cells that do not express mutant alpha-synuclein..Gem cells expressing A53T alpha-synuclein also presented reduced ER stress and increased ability to deal with oxidative stress. Together, our results suggest that deletion of Gem1 activates pathways that strengthen cells against other stressful agents such as the presence of mutant alpha-synuclein. (AU)

• FAPESP's process: 13/08028-1 - CEGH-CEL - Human Genome and Stem Cell Research Center
• Grantee: Mayana Zatz
• Support Opportunities: Research Grants - Research, Innovation and Dissemination Centers - RIDC
• FAPESP's process: 11/06434-7 - Degradation of hyperphosphorylated tau and organelles trafficking during neurodegenerative processes linked to protein aggregation in hypoccampal cell cultures
• Grantee: Merari de Fátima Ramires Ferrari
• Support Opportunities: Regular Research Grants
• FAPESP's process: 15/18961-2 - Study of autophagy as the driving mechanism of neurodegenerative diseases
• Grantee: Merari de Fátima Ramires Ferrari
• Support Opportunities: Regular Research Grants
• FAPESP's process: 18/07592-4 - The role of quality control mechanisms in the loss of proteostasis in age-dependent neurodegenerative diseases
• Grantee: Merari de Fátima Ramires Ferrari
• Support Opportunities: Regular Research Grants