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Therapeutic Promise and Insights for...

Benoit, Simon M.,

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Therapeutic Promise and Insights for Parkinson's Disease from the Living Brain /

Record Type:	Electronic resources : Monograph/item
Title/Author:	Therapeutic Promise and Insights for Parkinson's Disease from the Living Brain // Simon M Benoit.
Author:	Benoit, Simon M.,
Description:	1 electronic resource (259 pages)
Notes:	Source: Dissertations Abstracts International, Volume: 86-05, Section: B.
Contained By:	Dissertations Abstracts International86-05B.
Subject:	Neurodegeneration. -
Online resource:	https://pqdd.sinica.edu.tw/twdaoapp/servlet/advanced?query=31653196
ISBN:	9798346389538

Therapeutic Promise and Insights for Parkinson's Disease from the Living Brain /
Benoit, Simon M.,

Therapeutic Promise and Insights for Parkinson's Disease from the Living Brain /Simon M Benoit. - 1 electronic resource (259 pages)

Source: Dissertations Abstracts International, Volume: 86-05, Section: B.

Background: Parkinson's disease (PD) is a neurodegenerative disorder characterized by the progressive loss of dopaminergic neurons in the brain. To date, no disease-modifying treatments for PD are available and novel insights and therapeutics are essential. This thesis explores a novel substrate for cell-based therapies for PD, brain-derived progenitor cells (BDPCs), derived from living PD brain samples obtained during deep-brain stimulation surgery, while also utilizing this unique tissue source to gain important insights into the molecular underpinnings of the disease. Methods: In Chapter 2, human and rat BDPCs were compared, and the latter engineered for longitudinal tracking in vivo using bioluminescence imaging(BLI). The engineered cells were implanted in a rodent syngeneic graft model to evaluate BDPCs survival and integration after transplantation, mimicking an autologous therapeutic application. Chapters 3 and 4 utilized RNA sequencing to analyze gene expression and alternative splicing changes in the living PD frontal cortex. A random forest classifier was then trained on a 370-gene signature to discern PD samples from healthy controls. Results: Rodent BDPCs exhibited qualities analogous to their human counterparts, including expression and secretion of neurotrophic factors BDNF and GDNF. The rodent BDPC grafts could be tracked effectively with BLI, and showed survival and engraftment in the host brain. Transcriptomic profiling of the living PD brain revealed dysregulation of genes involved in trophic factor signaling, apoptosis, inflammation, and other key pathways. Numerous alternative splicing events were also found to be altered in PD. Building on these findings, a machine learning classifier was developed that could accurately distinguish PD samples from controls using the PD-associated gene expression signature, with potential applications for early diagnosis. Conclusions:This thesis establishes a preclinical platform to evaluate autologous BDPCs as a cell-based therapy for PD and provides unprecedented insights into the molecular landscape of the living PD brain. The identification of novel dysregulated pathways and splicing events, as well as the development of a diagnostic classifier, opens new avenues for understanding disease mechanisms and developing targeted (disease-modifying) interventions. The ability to directly access and interrogate the living PD brain represents a powerful approach to advance Parkinson's disease research.

English

ISBN: 9798346389538Subjects--Topical Terms:

3685376
Neurodegeneration.

Therapeutic Promise and Insights for Parkinson's Disease from the Living Brain /
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520 $a Background: Parkinson's disease (PD) is a neurodegenerative disorder characterized by the progressive loss of dopaminergic neurons in the brain. To date, no disease-modifying treatments for PD are available and novel insights and therapeutics are essential. This thesis explores a novel substrate for cell-based therapies for PD, brain-derived progenitor cells (BDPCs), derived from living PD brain samples obtained during deep-brain stimulation surgery, while also utilizing this unique tissue source to gain important insights into the molecular underpinnings of the disease. Methods: In Chapter 2, human and rat BDPCs were compared, and the latter engineered for longitudinal tracking in vivo using bioluminescence imaging(BLI). The engineered cells were implanted in a rodent syngeneic graft model to evaluate BDPCs survival and integration after transplantation, mimicking an autologous therapeutic application. Chapters 3 and 4 utilized RNA sequencing to analyze gene expression and alternative splicing changes in the living PD frontal cortex. A random forest classifier was then trained on a 370-gene signature to discern PD samples from healthy controls. Results: Rodent BDPCs exhibited qualities analogous to their human counterparts, including expression and secretion of neurotrophic factors BDNF and GDNF. The rodent BDPC grafts could be tracked effectively with BLI, and showed survival and engraftment in the host brain. Transcriptomic profiling of the living PD brain revealed dysregulation of genes involved in trophic factor signaling, apoptosis, inflammation, and other key pathways. Numerous alternative splicing events were also found to be altered in PD. Building on these findings, a machine learning classifier was developed that could accurately distinguish PD samples from controls using the PD-associated gene expression signature, with potential applications for early diagnosis. Conclusions:This thesis establishes a preclinical platform to evaluate autologous BDPCs as a cell-based therapy for PD and provides unprecedented insights into the molecular landscape of the living PD brain. The identification of novel dysregulated pathways and splicing events, as well as the development of a diagnostic classifier, opens new avenues for understanding disease mechanisms and developing targeted (disease-modifying) interventions. The ability to directly access and interrogate the living PD brain represents a powerful approach to advance Parkinson's disease research.
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