Wei Xiang (Germany)
University Hospital, FAU University Erlangen-Nürnberg, Germany
Department of Molecular Neurology
Wei Xiang is a research group leader at the Department of Molecular Neurology, University Hospital Erlangen, Friedrich-Alexander-University Erlangen-Nürnberg, Germany. Her research focuses on physiopathological structure and function of α-synculein and its aggregation in the pathogenesis of synucleinopathies, such as Parkinson’s disease and multiple system atrophy. Specifically, she investigates the role of molecular and cellular pathways, including microtubule organization, posttranslational modification of proteins, oxidative stress, and lysosomal autophagy pathway, in the induction and spreading of α-synculein pathology. Moreover, she is interested in modelling of human synucleinopathies with the use of human induced pluripotent stem cells.

Presenter of 1 Presentation

 Conference Calendar

SNCA DUPLICATION IS SUFFICIENT TO INDUCE NEURITIC AND NEURONAL DEGENERATION IN HUMAN-INDUCED PLURIPOTENT STEM CELL-DERIVED DOPAMINERGIC NEURONS FROM PATIENTS OF PARKINSON’S DISEASE

Session Name
0640 - SINGLE-CELL GENOMICS STEM CELLS 3 (ID 34)
Session Type
SYMPOSIUM
Date
Thu, 17.03.2022
Session Time
09:10 AM - 11:10 AM
Room
ONSITE: 113
Lecture Time
09:25 AM - 09:40 AM
Presenter

Abstract

Aims

Parkinson’s disease (PD) is neuropathologically characterized by the deposition of aggregated alpha-synuclein (aSyn) and the loss of midbrain dopaminergic neurons (mDANs), preceded by neuritic degeneration. Point mutations and multiplications of aSyn gene (SNCA) have been associated with the familial forms of PD (fPD), indicating a crucial role of aSyn in the pathogenesis of PD. In contrast to age-related sporadic PD (sPD), fPDs are frequently linked to an early onset, a rapid progression and a severe aSyn pathology. In this study, we aimed to prove the hypothesis that SNCA dosage increase is the primary trigger of aSyn pathology and mDAN degeneration in fPD with SNCA multiplication.

Methods

We generated mDANs from human-induced pluripotent stem cells (hiPSC) derived from fPD patients carrying a SNCA duplication (SNCADupl) and compared their phenotypes to those of mDANs from sPD patients and healthy controls.

Results

We observed a significant increase of aSyn levels and aggregation in SNCADupl-mDANs, accompanied by neurite impairments. Biochemical analyses further revealed SNCADupl-mediated perturbations in microtubule organization. Moreover, an increased basal apoptotic rate was specifically detected in SNCADupl-mDANs. By contrast, mDANs from sPD patients did not exhibit marked changes in aSyn homeostasis, neuronal morphology, and neuritic activity. sPD-mDANs showed deficits in neurite outgrowth only, when exposed to exogenous stress, such as autophagy inhibition.

Conclusions

Our studies using the identical human mDAN model system indicate that mDANs from SNCADupl PD patients are severely impaired even under steady-state conditions. Moreover, SNCADupl-induced aSyn overload is sufficient to cause PD-related aSyn pathology and neurodegeneration.

Hide