Exploring Patient-Specific Cell Replacement Therapy for Parkinson's Disease

Research output: ThesisDoctoral Thesis (compilation)

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Abstract

Parkinson’s disease (PD) affects over six million people worldwide and is characterised by the progressive loss of dopaminergic (DA) neurons in the substantia nigra, accumulation of pathological alpha-synuclein (αSyn), and inflammation in the brain. This leads to motor impairments including rigidity, akinesia, bradykinesia, resting tremor, and postural instability. Cell replacement therapy aims to replace the midbrain DA neurons which have been lost in the disease to restore normal motor function. Previously, DA cells for transplantation have been derived from fetal mesencephalic tissue or human embryonic stem cells (hESCs). However, an alternative route to generate DA cells is via cellular reprogramming. This is a rapidly emerging field which allows somatic cells to be reprogrammed either into human induced pluripotent stem cells (hiPSCs) or directly into induced neurons (iNs) by forced expression of specific factors. This creates the possibility to use patient-specific cells which could reduce the risk of immune rejection and eliminate ethical concerns.

The overall aim of this thesis is to evaluate if patient-derived cells could be a suitable alternative in cell replacement therapy for PD. Firstly, an efficient protocol to directly reprogram human adult fibroblasts into iNs was developed. Following this, factors that could convert cells specifically towards a DA subtype were investigated and used to examine if cells from healthy donors and PD patients could be reprogrammed with similar efficiency. Next, a new humanized αSyn xenograft model of PD was established to assess the impact of host pathology on grafted cells. Finally, we explored if DA cells derived from a patient hiPSC line harbouring an αSyn triplication mutation could survive intracerebral transplantation and function on par with hESC-derived DA neurons. This patient line was also assessed for the presence of pathological features in different models of PD. These results will help to pave the way for future research assessing the potential of patient-derived cells for brain repair.
Original languageEnglish
QualificationDoctor
Awarding Institution
  • Department of Experimental Medical Science
Supervisors/Advisors
  • Parmar, Malin, Supervisor
  • Lundberg, Cecilia, Assistant supervisor
  • Hoban, Deirdre, Assistant supervisor
Award date2021 Mar 12
Place of PublicationLund
Publisher
Print ISBNs978-91-8021-026-3
Publication statusPublished - 2021

Bibliographical note

Defence details
Date: 2021-03-12
Time: 09:00
Place: Segerfalksalen, BMC A10, Sölvegatan 17 i Lund. Join by Zoom: https://lu-se.zoom.us/j/62063710446
External reviewer(s)
Name: Meyer, Morten
Title: associate professor
Affiliation: University of Southern Denmark, Odense, Denmark.

Subject classification (UKÄ)

  • Neurosciences

Keywords

  • dopaminergic neurons
  • Parkinson's disease
  • cell replacement therapy
  • cellular reprogramming
  • alpha-synuclein

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