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Investigation of alpha-synuclein pathology in Parkinson's disease

Li, Wen LU (2018)
Abstract
Abstract
Parkinson's disease (PD) is one of the most common neurodegenerative diseases in humans. It is a slowly progressing neurological disorder exhibiting major symptoms including resting tremor, rigidity, bradykinesia and postural instability. PD also gives rise to non-motor symptoms such as loss of olfaction, gastrointestinal system disruption, cognitive functional decline, etc. The loss of dopaminergic neurons in the substantia nigra and the formation of abnormal protein aggregates (Lewy bodies (LBs)) intracellularly are the two main pathological changes observed in PD patient brains.
Currently, pharmacological therapy using levodopa (L-DOPA) is the main method of treating PD. One potential therapeutic method is the... (More)
Abstract
Parkinson's disease (PD) is one of the most common neurodegenerative diseases in humans. It is a slowly progressing neurological disorder exhibiting major symptoms including resting tremor, rigidity, bradykinesia and postural instability. PD also gives rise to non-motor symptoms such as loss of olfaction, gastrointestinal system disruption, cognitive functional decline, etc. The loss of dopaminergic neurons in the substantia nigra and the formation of abnormal protein aggregates (Lewy bodies (LBs)) intracellularly are the two main pathological changes observed in PD patient brains.
Currently, pharmacological therapy using levodopa (L-DOPA) is the main method of treating PD. One potential therapeutic method is the transplantation of fetal dopaminergic neurons into PD patient brains to replace the lost dopaminergic neurons. This approach has been shown to be effective in a number of clinical trials. However, there exists large variation amongst different cases. One of the reasons contributing to the failure in some transplantation trials may be the presence of LBs in the transplanted neurons.
The main protein component of LBs is alpha-synuclein. Alpha-synuclein is a synaptic protein with unclear physiological functions. It has been reported that this protein may be related to neurotransmitter release. Alpha-synuclein aggregates can spread from one cell to another and from the peripheral tissue to the brain. Alpha-synuclein pathology may cause multiple cellular dysfunctions, including mitochondrial deficiencies. It has been reported that in PD, mitochondrial function is inhibited, however, the link between alpha-synuclein aggregation, propagation and mitochondrial dysfunction has not yet been clearly defined.
Therefore, in this thesis, we first investigated the presence of alpha-synuclein aggregates in the brains of four PD patients who received fetal dopaminergic grafts 12-24 years before death, aiming to investigate the development of graft Lewy pathology, in relation to host Lewy pathology profiles. We observed survived grafted neurons in the four patient brains, and the grafts all developed Lewy pathology, as observed from postmortem analysis. We also analyzed the relationship between graft age and severity of host Lewy pathology and graft Lewy pathology developments. We found a positive correlation between host Lewy pathology and graft Lewy body accumulation.
Subsequently, we examined the toxic effects of preformed alpha-synuclein fibrils towards mitochondrial motility and respiration in PD models. We discovered that aggregated alpha-synuclein can cause mitochondrial trafficking deficiency and respiration dysfunction.
This thesis provides a comprehensive discussion of alpha-synuclein pathology in PD, expanding from protein propagation to cellular toxicity. It may serve as an inspiration and a reference for the future in depth understanding of PD disease mechanisms and for finding potential and effective therapeutic approaches for PD.

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author
supervisor
opponent
  • professor Kordower, Jeffrey, Rush University, Chicago, USA
organization
publishing date
type
Thesis
publication status
published
subject
keywords
Parkinson's disease, alpha-synuclein, mitochondria, propagation
pages
100 pages
publisher
Lund University, Faculty of Medicine
defense location
Segerfalksalen, BMC A10, Sölvegatan 17 i Lund
defense date
2018-03-08 09:15
ISBN
978-91-7619-585-7
language
English
LU publication?
yes
id
89556eae-cf4e-4722-b99a-23bcc92edf74
date added to LUP
2018-02-13 12:23:08
date last changed
2019-03-07 14:24:37
@phdthesis{89556eae-cf4e-4722-b99a-23bcc92edf74,
  abstract     = {Abstract<br/>Parkinson's disease (PD) is one of the most common neurodegenerative diseases in humans. It is a slowly progressing neurological disorder exhibiting major symptoms including resting tremor, rigidity, bradykinesia and postural instability. PD also gives rise to non-motor symptoms such as loss of olfaction, gastrointestinal system disruption, cognitive functional decline, etc. The loss of dopaminergic neurons in the substantia nigra and the formation of abnormal protein aggregates (Lewy bodies (LBs)) intracellularly are the two main pathological changes observed in PD patient brains. <br/>Currently, pharmacological therapy using levodopa (L-DOPA) is the main method of treating PD. One potential therapeutic method is the transplantation of fetal dopaminergic neurons into PD patient brains to replace the lost dopaminergic neurons. This approach has been shown to be effective in a number of clinical trials. However, there exists large variation amongst different cases. One of the reasons contributing to the failure in some transplantation trials may be the presence of LBs in the transplanted neurons. <br/>The main protein component of LBs is  alpha-synuclein.  Alpha-synuclein is a synaptic protein with unclear physiological functions. It has been reported that this protein may be related to neurotransmitter release.  Alpha-synuclein aggregates can spread from one cell to another and from the peripheral tissue to the brain.  Alpha-synuclein pathology may cause multiple cellular dysfunctions, including mitochondrial deficiencies. It has been reported that in PD, mitochondrial function is inhibited, however, the link between  alpha-synuclein aggregation, propagation and mitochondrial dysfunction has not yet been clearly defined. <br/>Therefore, in this thesis, we first investigated the presence of  alpha-synuclein aggregates in the brains of four PD patients who received fetal dopaminergic grafts 12-24 years before death, aiming to investigate the development of graft Lewy pathology, in relation to host Lewy pathology profiles. We observed survived grafted neurons in the four patient brains, and the grafts all developed Lewy pathology, as observed from postmortem analysis. We also analyzed the relationship between graft age and severity of host Lewy pathology and graft Lewy pathology developments. We found a positive correlation between host Lewy pathology and graft Lewy body accumulation.<br/>Subsequently, we examined the toxic effects of preformed  alpha-synuclein fibrils towards mitochondrial motility and respiration in PD models. We discovered that aggregated  alpha-synuclein can cause mitochondrial trafficking deficiency and respiration dysfunction. <br/>This thesis provides a comprehensive discussion of  alpha-synuclein pathology in PD, expanding from protein propagation to cellular toxicity. It may serve as an inspiration and a reference for the future in depth understanding of PD disease mechanisms and for finding potential and effective therapeutic approaches for PD. <br/><br/>},
  author       = {Li, Wen},
  isbn         = {978-91-7619-585-7},
  keyword      = {Parkinson's disease,  alpha-synuclein, mitochondria, propagation},
  language     = {eng},
  pages        = {100},
  publisher    = {Lund University, Faculty of Medicine},
  school       = {Lund University},
  title        = {Investigation of alpha-synuclein pathology in Parkinson's disease},
  year         = {2018},
}