Veronika Sigutova (Germany)
University Hospital Erlangen
Department of Stem Cell Biology
I am currently a second-year PhD student in the Neuroimmunology working group at the Department of Stem Cell Biology, University Hospital Erlangen. My project focuses on the crosstalk of adaptive immunity and alpha-synuclein pathology in stem-cell-derived neuronal models of Parkinson's disease. Specifically, I am interested in whether cytokines aggravate axonal deficits and alpha-synuclein aggregation in dopamine neurons with SNCA duplication. I have completed my BSc in Biomedical Science with a third-year specialisation in Neuroscience and Mental Health at Imperial College London. I undertook the Bachelor thesis at Montreal Neurological Institute in the group of Prof. Stefano Stifani, investigating the activation of the NF-κB pathway in iPSC-derived ALS astrocytes with SOD1 mutation. I continued with MSc in Neuroscience at the University of Oxford where I did two quite different Master theses: one in the lab of Prof. Zoltan Molnar, looking at the effect of layer 5 projection neuron silencing on parvalbumin interneurons, and the second one in the Heart and Brain Group led by Dr. Sana Suri, examining the association between the longitudinal change in white matter hyperintensities, midlife cardiovascular health and later-life cognition. I have a general interest in non-cell-autonomous mechanisms of neurodegenerative diseases using cellular and molecular techniques.

Presenter of 1 Presentation

 Conference Calendar

REDUCING ALPHA-SYNUCLEIN OLIGOMERISATION RESCUES MITOCHONDRIAL-SPECIFIC PATHOLOGY OF MIDBRAIN NEURONS IN PARKINSON’S DISEASE

Session Name
1080 - ALPHA-SYNUCLEIN- DISEASE MECHANISMS, DETECTION & THERAPEUTIC RELEVANCE (ID 53)
Session Type
SYMPOSIUM
Date
Fri, 18.03.2022
Session Time
09:10 AM - 11:10 AM
Room
ONSITE: 114
Lecture Time
09:40 AM - 09:55 AM
Presenter

Abstract

Aims

Parkinson’s disease (PD) is characterised by a progressive loss of midbrain dopaminergic neurons (mDANs) and protein inclusions mostly consisting of α-synuclein (α-syn) aggregates. α-Syn aggregation is a central PD hallmark, and its oligomers are purportedly the most neurotoxic species representing early PD pathology. This includes cell compartment-specific toxicity to mitochondria, widespread across different forms of PD. Hence, inhibiting α-syn oligomerisation may represent a promising disease-modifying strategy, which we used here to improve mitochondrial-specific pathology in PD mDANs.

Methods

mDANs were differentiated from induced pluripotent stem cells derived from PD patients with α-syn gene locus duplication and control individuals. mDANs were treated with a novel α-syn anti-oligomerisation compound NPT100-18A, DMSO or left untreated, and assessed for several mitochondrial phenotypes, α-syn aggregation, and cell death.

Results

While the levels of cytoplasmic oxidative stress and extracellular nitrogen species were comparable between control- and PD-derived mDANs, PD mDANs exhibited higher mitochondrial pathology presenting as reduced basal ATP levels, increased basal mitochondrial superoxide, as well as increased cell death and enhanced α-syn insolubility. Inhibition of α-syn oligomerisation by NPT100-18A rescued specifically PD mDAN mitochondrial oxidative stress and cell death. Interfering with α-syn oligomerisation is thus a viable strategy for rescuing the cell-compartment specific pathology in the vulnerable mDANs in a human-relevant model.

Conclusions

Our findings confirm and expand on our previous results indicating that pathogenic α-syn contributes to the selective vulnerability of mDANs in PD, and demonstrate the therapeutic potential of reducing α-syn oligomerisation on mitochondrial pathology, one of the key hallmarks of PD.

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