Kaitlyn M. Cramb (United Kingdom)
University of Oxford
Department of Physiology, Anatomy & Genetics
Kaitlyn completed a Bachelors of Science in Microbiology & Immunology at the University of British Columbia and went on to complete a Masters of Science in Cell Biology at ETH Zurich. A recipient of the Natural Sciences and Engineering Council of Canada's Postgraduate Award, St. John's College Lester B. Pearson award and the Clarendon Award, she is currently working towards achieving her DPhil in the laboratory of Richard Wade-Martins in the Department of Physiology, Anatomy & Genetics at the University of Oxford. Kaitlyn uses iPSC-derived dopamine neurons from Parkinson's affected individuals to examine molecular mechanisms leading to dysfunction in the human PD brain. Kaitlyn's project specifically focuses on producing these cells to investigate mechanisms of defective dopamine release and synaptic dysfunction in PD. This research is important for understanding the pathophysiology of PD and the discovery of novel targets for future therapeutics.

Presenter of 1 Presentation

 Conference Calendar

DOPAMINE RELEASE IS DEFECTIVE IN IPSC-DERIVED DOPAMINE NEURONS HARBOURING PARKINSON’S DISEASE-ASSOCIATED SNCA-TRIPLICATION

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
10:40 AM - 10:55 AM
Presenter

Abstract

Aims

Parkinson’s disease (PD) is a disorder in which the degeneration of dopaminergic neurons (DAns) in the nigrostriatal pathway leads to debilitating motor symptoms. There remains to be a unifying hypothesis for how this degeneration is initiated and because of this, no disease-modifying therapeutics are available. Evidence from several animal models of familial PD indicates that defective dopamine release is an early cardinal feature of PD, preceding both neurodegeneration and symptom onset. Therefore, we aim to address whether dopamine release is dysfunctional in human dopamine neurons from PD-affected individuals and the molecular mechanisms by which this occurs.

Methods

We produced induced pluripotent stem cell (iPSC)-derived dopamine neurons from patients with PD-associated mutation SNCA-triplication using a modified Krik’s protocol. KCl-evoked dopamine release and total intracellular dopamine content were measured using high performance liquid chromatography electrochemical detection (HPLC-ECD) and synaptic defects were measured using whole-cell patch-clamp electrophysiology.

Results

We observed a ninety percent decrease in evoked dopamine release from iPSC-DAns harbouring SNCA-triplication and found that this coincides with a decrease in total intracellular dopamine content of the same magnitude. Both defective release and content were restored by acute L-DOPA treatment. Further data supports that these defects are not due to defective dopamine synthesis, but rather alterations in its handling. These defects in dopamine release and content coincide with electrophysiological dysfunction.

Conclusions

Combined, these data provide support from human models that synaptic dysfunction occurs early in PD. This study will be critical to providing novel targets for the development of effective disease-modifying therapeutics.

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