Dissection of the genetic architecture in Caenorhabditis elegans underlying protein misfolding pathological mechanisms

Yiru A. Wang, M.G. Sterken, J.E. Kammenga, S.C. Harvey

Research output: Contribution to conferencePosterAcademic

Abstract

Neurodegenerative diseases like Alzheimer's-disease (AD) and Parkinson's-disease (PD) represent an increasing threat to human health. Despite progress in identification of several AD and PD related genes, the effect of alleles underlying protein misfolding in these diseases remains unclear. Given the molecular conservation in essential signalling between the model organism C. elegans and humans, transgenic worms that express aggregating proteins have been created for studying the onset and progression of these diseases and the functional alleles that affect them. For example, analysis of transgenic worms expressing the human synaptic protein alpha-synuclein, of which accumulation is causative of PD, have identified links between its proteotoxicity and insulin/insulin-like growth factor (IGF), mitochondrial dysfunction, and aging. The evolutionary forces drive genome generation, and natural variants show impacts on molecular and cellular processes, leading to complex organismal phenotypes in plants, worms, flies, rodents as well as humans. However, previous researches that solely rely on induced mutants in canonical N2 limit the ability to explore how naturally varying alleles alter signalling pathways, including investigation on protein misfolding disease pathological mechanisms. Our research aims to go beyond classical mutant screens on the genetic pathway analysis of complex traits, i.e. phenotypic differences among individuals, to also consider the allelic interactions in different genetic backgrounds. We have therefore introgressed the PD transgene (unc-54: α-Syn:YFP) into four different wild isolate genetic backgrounds. Analysis of life history in these new introgressed lines indicates that the transgene effects vary greatly depending on the background. This is a necessary and important step to generally understand the influence of natural variation of the genetic background on the disease progressing mechanism.
Original languageEnglish
Pages236-236
Publication statusPublished - May 2016
EventEuropean Worm Meeting (EWM) 2016 - Max Delbrück Center (MDC), Berlin, Germany
Duration: 1 Jun 20163 Jun 2016

Conference

ConferenceEuropean Worm Meeting (EWM) 2016
CountryGermany
CityBerlin
Period1/06/163/06/16

Fingerprint

Caenorhabditis elegans Proteins
Parkinson Disease
Dissection
Proteostasis Deficiencies
Alleles
Transgenes
Alzheimer Disease
alpha-Synuclein
Aptitude
Caenorhabditis elegans
Somatomedins
Research
Individuality
Diptera
Neurodegenerative Diseases
Disease Progression
Rodentia
Proteins
Genome
Insulin

Cite this

Wang, Y. A., Sterken, M. G., Kammenga, J. E., & Harvey, S. C. (2016). Dissection of the genetic architecture in Caenorhabditis elegans underlying protein misfolding pathological mechanisms. 236-236. Poster session presented at European Worm Meeting (EWM) 2016, Berlin, Germany.
Wang, Yiru A. ; Sterken, M.G. ; Kammenga, J.E. ; Harvey, S.C. / Dissection of the genetic architecture in Caenorhabditis elegans underlying protein misfolding pathological mechanisms. Poster session presented at European Worm Meeting (EWM) 2016, Berlin, Germany.
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Dissection of the genetic architecture in Caenorhabditis elegans underlying protein misfolding pathological mechanisms. / Wang, Yiru A.; Sterken, M.G.; Kammenga, J.E.; Harvey, S.C.

2016. 236-236 Poster session presented at European Worm Meeting (EWM) 2016, Berlin, Germany.

Research output: Contribution to conferencePosterAcademic

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AB - Neurodegenerative diseases like Alzheimer's-disease (AD) and Parkinson's-disease (PD) represent an increasing threat to human health. Despite progress in identification of several AD and PD related genes, the effect of alleles underlying protein misfolding in these diseases remains unclear. Given the molecular conservation in essential signalling between the model organism C. elegans and humans, transgenic worms that express aggregating proteins have been created for studying the onset and progression of these diseases and the functional alleles that affect them. For example, analysis of transgenic worms expressing the human synaptic protein alpha-synuclein, of which accumulation is causative of PD, have identified links between its proteotoxicity and insulin/insulin-like growth factor (IGF), mitochondrial dysfunction, and aging. The evolutionary forces drive genome generation, and natural variants show impacts on molecular and cellular processes, leading to complex organismal phenotypes in plants, worms, flies, rodents as well as humans. However, previous researches that solely rely on induced mutants in canonical N2 limit the ability to explore how naturally varying alleles alter signalling pathways, including investigation on protein misfolding disease pathological mechanisms. Our research aims to go beyond classical mutant screens on the genetic pathway analysis of complex traits, i.e. phenotypic differences among individuals, to also consider the allelic interactions in different genetic backgrounds. We have therefore introgressed the PD transgene (unc-54: α-Syn:YFP) into four different wild isolate genetic backgrounds. Analysis of life history in these new introgressed lines indicates that the transgene effects vary greatly depending on the background. This is a necessary and important step to generally understand the influence of natural variation of the genetic background on the disease progressing mechanism.

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Wang YA, Sterken MG, Kammenga JE, Harvey SC. Dissection of the genetic architecture in Caenorhabditis elegans underlying protein misfolding pathological mechanisms. 2016. Poster session presented at European Worm Meeting (EWM) 2016, Berlin, Germany.