The effect of mutant GBA1 on accumulation and aggregation of a synuclein

Gali Maor, Debora Rapaport, Mia Horowitz

Research output: Contribution to journalArticlepeer-review

Abstract

Gaucher disease (GD) patients and carriers of GD mutations have a higher propensity to develop Parkinsons disease (PD) in comparison to the non-GD population. This implies that mutant GBA1 allele is a predisposing factor for the development of PD. One of the major characteristics of PD is the presence of oligomeric ?-synuclein-positive inclusions known as Lewy bodies in the dopaminergic neurons localized to the substantia nigra pars compacta. In the present study we tested whether presence of human mutant GCase leads to accumulation and aggregation of ?-synuclein in two models: in SHSY5Y neuroblastoma cells endogenously expressing ?-synuclein and stably transfected with human GCase variants, and in Drosophila melanogaster co-expressing normal human ?-synuclein and mutant human GCase. Our results showed that heterologous expression of mutant, but not WT, human GCase in SHSY5Y cells, led to a significant stabilization of ?-synuclein and to its aggregation. In parallel, there was also a significant stabilization of mutant, but not WT, GCase. Co-expression of human ?-synuclein and human mutant GCase in the dopaminergic cells of flies initiated ?-synuclein aggregation, earlier death of these cells and significantly shorter life span, compared with flies expressing ?-synuclein or mutant GCase alone. Taken together, our results strongly indicate that human mutant GCase contributes to accumulation and aggregation of ?-synuclein. In the f ly, this aggregation leads to development of more severe parkinsonian signs in comparison to flies expressing either mutant GCase or ?-synuclein alone.

Original languageEnglish
Pages (from-to)1768-1781
Number of pages14
JournalHuman Molecular Genetics
Volume28
Issue number11
DOIs
StatePublished - 1 Jun 2019

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