Aggregation and toxicity study of Parkinson’s Disease related mutations in α-Synuclein.
(2016) KEML13 20161Department of Chemistry
- Abstract
- Parkinson´s Disease is the second most common neurodegenerative disease. Only a small number of cases appear to be caused by genetic mutations, meaning most cases arise due to unknown mechanisms. While there are reported to be multiple causes of the disease, what links all cases is a small protein called α-synuclein whose aggregation appears to correlate to the pathology and progression of the disease. So far, five point mutations have been identified to trigger PD pathology at various ages (often early) of onset. The mutations has also shown diversity in physical properties of the protein. Considering this fact, the aim of this thesis was to investigate the mutations ability to change aggregation kinetics of α-synuclein but also its... (More)
- Parkinson´s Disease is the second most common neurodegenerative disease. Only a small number of cases appear to be caused by genetic mutations, meaning most cases arise due to unknown mechanisms. While there are reported to be multiple causes of the disease, what links all cases is a small protein called α-synuclein whose aggregation appears to correlate to the pathology and progression of the disease. So far, five point mutations have been identified to trigger PD pathology at various ages (often early) of onset. The mutations has also shown diversity in physical properties of the protein. Considering this fact, the aim of this thesis was to investigate the mutations ability to change aggregation kinetics of α-synuclein but also its impact on cellular toxicity. To examine the time dependent uptake in presence of extracellular vesicles was also of importance as these vesicles have previously been shown to influence α-synuclein aggregation. The uptake result showed that α-synuclein could be taken up approximately three times more in presence of extracellular vesicles. The cellular toxicity study revealed that toxicity performed in the presence of 1µM αSyn didn’t result in significant levels of toxicity, but we could see that cellular toxicity is increased by using higher concentration of α-synuclein and by combining α-synuclein with vesicles. The aggregation studies showed that point mutation could have a great impact on the protein properties but the number of trials didn’t leave a space to conclude anything. All together, I have generated a number of valuable tools that have the potential to be used in a number of scientific studies in the future. (Less)
- Popular Abstract (Swedish)
- Parkinsons sjukdom är en neurologisk sjukdom som drabbar upp till 2 % av alla människor över 60 år. De exakta orsakerna som leder till utvecklingen av sjukdomen är fortfarande okända men åldrandet är den största kända riskfaktorn idag. Sjukdomen kännetecknas av en progressiv försämring av kroppens rörelseförmåga i samband med förlust av nervceller. Patienter med sjukdomen har också påvisat protein ansamlingar i hjärnan (så kallade Lewykroppar) som till största del består av α-Synuclein. α-Synuclein är ett litet protein som är mest anrikad i hjärnan. I dag är man säker på att fem stycken mutationer i proteinet (A30P, E46K, H50Q, H51D and A53T) leder till en utveckling av Parkinson sjukdomen. Hur exakt mutationerna leder till... (More)
- Parkinsons sjukdom är en neurologisk sjukdom som drabbar upp till 2 % av alla människor över 60 år. De exakta orsakerna som leder till utvecklingen av sjukdomen är fortfarande okända men åldrandet är den största kända riskfaktorn idag. Sjukdomen kännetecknas av en progressiv försämring av kroppens rörelseförmåga i samband med förlust av nervceller. Patienter med sjukdomen har också påvisat protein ansamlingar i hjärnan (så kallade Lewykroppar) som till största del består av α-Synuclein. α-Synuclein är ett litet protein som är mest anrikad i hjärnan. I dag är man säker på att fem stycken mutationer i proteinet (A30P, E46K, H50Q, H51D and A53T) leder till en utveckling av Parkinson sjukdomen. Hur exakt mutationerna leder till sjukdomsutvecklingen är fortfarande okänd. Det finns en teori som säger att mutationerna orsakar en felvekning i proteinet som i sin tur påskyndar proteinets aggregering (monomer - oligomer - fibrill). I detta arbete visades att mutanterna resulterar i en varierande aggregation mönster jämfört med den icke muterade α-Synuclein. Det intressanta är att kliniska studier också har visat att mutationerna leder till varierande symptom och sjukdomsförlopp hos patienter. Det är fortfarande obestämd vilket form av α-Synuclein som är mest toxisk men fibriller är dom enda aggregaten som inte löser sig i cytoplasman. Ansamling av dessa former inuti cellen skulle kunna leda till störning av cellulära process och eventuellt cell död. I detta arbete kan man se att α-Synuclein i högre koncentration orsakar högre toxicitet och ett protein i högre koncentration aggregerar snabbare överlag. (Less)
Please use this url to cite or link to this publication:
http://lup.lub.lu.se/student-papers/record/8886638
- author
- Labecka, Nikol LU
- supervisor
- organization
- course
- KEML13 20161
- year
- 2016
- type
- M2 - Bachelor Degree
- subject
- keywords
- Parkinson’s Disease, α-Synuclein, biochemistry, biokemi
- language
- English
- id
- 8886638
- date added to LUP
- 2016-08-01 17:06:46
- date last changed
- 2016-08-01 17:06:46
@misc{8886638,
abstract = {{Parkinson´s Disease is the second most common neurodegenerative disease. Only a small number of cases appear to be caused by genetic mutations, meaning most cases arise due to unknown mechanisms. While there are reported to be multiple causes of the disease, what links all cases is a small protein called α-synuclein whose aggregation appears to correlate to the pathology and progression of the disease. So far, five point mutations have been identified to trigger PD pathology at various ages (often early) of onset. The mutations has also shown diversity in physical properties of the protein. Considering this fact, the aim of this thesis was to investigate the mutations ability to change aggregation kinetics of α-synuclein but also its impact on cellular toxicity. To examine the time dependent uptake in presence of extracellular vesicles was also of importance as these vesicles have previously been shown to influence α-synuclein aggregation. The uptake result showed that α-synuclein could be taken up approximately three times more in presence of extracellular vesicles. The cellular toxicity study revealed that toxicity performed in the presence of 1µM αSyn didn’t result in significant levels of toxicity, but we could see that cellular toxicity is increased by using higher concentration of α-synuclein and by combining α-synuclein with vesicles. The aggregation studies showed that point mutation could have a great impact on the protein properties but the number of trials didn’t leave a space to conclude anything. All together, I have generated a number of valuable tools that have the potential to be used in a number of scientific studies in the future.}},
author = {{Labecka, Nikol}},
language = {{eng}},
note = {{Student Paper}},
title = {{Aggregation and toxicity study of Parkinson’s Disease related mutations in α-Synuclein.}},
year = {{2016}},
}