Integrated analysis of transcriptomic and proteomic alterations in mouse models of ALS/FTD identify early metabolic adaptions with similarities to mitochondrial dysfunction disorders
Sporadic and familial amyotrophic lateral sclerosis (ALS) is a fatal progressive neurodegenerative disease that results in loss of motor neurons and, in some patients, associates with frontotemporal dementia (FTD). Apart from the accumulation of proteinaceous deposits, emerging literature indicates...
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Published in | Amyotrophic lateral sclerosis and frontotemporal degeneration Vol. 25; no. 1-2; p. 135 |
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Main Authors | , , , , , , , , , , , , , , , , , , , , , , |
Format | Journal Article |
Language | English |
Published |
England
01.02.2024
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Abstract | Sporadic and familial amyotrophic lateral sclerosis (ALS) is a fatal progressive neurodegenerative disease that results in loss of motor neurons and, in some patients, associates with frontotemporal dementia (FTD). Apart from the accumulation of proteinaceous deposits, emerging literature indicates that aberrant mitochondrial bioenergetics may contribute to the onset and progression of ALS/FTD. Here we sought to investigate the pathophysiological signatures of mitochondrial dysfunction associated with ALS/FTD.
By means of label-free mass spectrometry (MS) and mRNA sequencing (mRNA-seq), we report pre-symptomatic changes in the cortices of TDP-43 and FUS mutant mouse models. Using tissues from transgenic mouse models of mitochondrial diseases as a reference, we performed comparative analyses and extracted unique and common mitochondrial signatures that revealed neuroprotective compensatory mechanisms in response to early damage.
In this regard, upregulation of both Acyl-CoA Synthetase Long-Chain Family Member 3 (ACSL3) and mitochondrial tyrosyl-tRNA synthetase 2 (YARS2) were the most representative change in pre-symptomatic ALS/FTD tissues, suggesting that fatty acid beta-oxidation and mitochondrial protein translation are mechanisms of adaptation in response to ALS/FTD pathology.
Together, our unbiased integrative analyses unveil novel molecular components that may influence mitochondrial homeostasis in the earliest phase of ALS. |
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AbstractList | Sporadic and familial amyotrophic lateral sclerosis (ALS) is a fatal progressive neurodegenerative disease that results in loss of motor neurons and, in some patients, associates with frontotemporal dementia (FTD). Apart from the accumulation of proteinaceous deposits, emerging literature indicates that aberrant mitochondrial bioenergetics may contribute to the onset and progression of ALS/FTD. Here we sought to investigate the pathophysiological signatures of mitochondrial dysfunction associated with ALS/FTD.
By means of label-free mass spectrometry (MS) and mRNA sequencing (mRNA-seq), we report pre-symptomatic changes in the cortices of TDP-43 and FUS mutant mouse models. Using tissues from transgenic mouse models of mitochondrial diseases as a reference, we performed comparative analyses and extracted unique and common mitochondrial signatures that revealed neuroprotective compensatory mechanisms in response to early damage.
In this regard, upregulation of both Acyl-CoA Synthetase Long-Chain Family Member 3 (ACSL3) and mitochondrial tyrosyl-tRNA synthetase 2 (YARS2) were the most representative change in pre-symptomatic ALS/FTD tissues, suggesting that fatty acid beta-oxidation and mitochondrial protein translation are mechanisms of adaptation in response to ALS/FTD pathology.
Together, our unbiased integrative analyses unveil novel molecular components that may influence mitochondrial homeostasis in the earliest phase of ALS. |
Author | Dillon, Eugène T Wischhof, Lena Hogg, Marion Farrell, Cliona Watters, Orla Matveeva, Anna Connolly, Niamh M C Woods, Ina Matallanas, David Perez, Ivan Fernandez Muñoz, Amaya Garcia Khemka, Niraj Lo Cacciato, Elide Lambrechts, Diether Bano, Daniele Llorente-Folch, Irene Halang, Luise Rukhadze, Ani Jackson, Joshua Piazzesi, Antonia Gentile, Debora Prehn, Jochen H M Arijs, Ingrid |
Author_xml | – sequence: 1 givenname: Anna surname: Matveeva fullname: Matveeva, Anna organization: Department of Physiology and Medical Physics, Royal College of Surgeons in Ireland, Dublin 2, Ireland – sequence: 2 givenname: Orla surname: Watters fullname: Watters, Orla organization: SFI FutureNeuro Research Centre, Dublin 2, Ireland – sequence: 3 givenname: Ani surname: Rukhadze fullname: Rukhadze, Ani organization: German Center for Neurodegenerative Diseases (DZNE), Bonn, Germany – sequence: 4 givenname: Niraj surname: Khemka fullname: Khemka, Niraj organization: Department of Physiology and Medical Physics, Royal College of Surgeons in Ireland, Dublin 2, Ireland – sequence: 5 givenname: Debora surname: Gentile fullname: Gentile, Debora organization: German Center for Neurodegenerative Diseases (DZNE), Bonn, Germany – sequence: 6 givenname: Ivan Fernandez surname: Perez fullname: Perez, Ivan Fernandez organization: Department of Physiology and Medical Physics, Royal College of Surgeons in Ireland, Dublin 2, Ireland – sequence: 7 givenname: Irene surname: Llorente-Folch fullname: Llorente-Folch, Irene organization: Department of Physiology and Medical Physics, Royal College of Surgeons in Ireland, Dublin 2, Ireland – sequence: 8 givenname: Cliona surname: Farrell fullname: Farrell, Cliona organization: Department of Physiology and Medical Physics, Royal College of Surgeons in Ireland, Dublin 2, Ireland – sequence: 9 givenname: Elide surname: Lo Cacciato fullname: Lo Cacciato, Elide organization: German Center for Neurodegenerative Diseases (DZNE), Bonn, Germany – sequence: 10 givenname: Joshua surname: Jackson fullname: Jackson, Joshua organization: German Center for Neurodegenerative Diseases (DZNE), Bonn, Germany – sequence: 11 givenname: Antonia surname: Piazzesi fullname: Piazzesi, Antonia organization: German Center for Neurodegenerative Diseases (DZNE), Bonn, Germany – sequence: 12 givenname: Lena surname: Wischhof fullname: Wischhof, Lena organization: German Center for Neurodegenerative Diseases (DZNE), Bonn, Germany – sequence: 13 givenname: Ina surname: Woods fullname: Woods, Ina organization: Department of Physiology and Medical Physics, Royal College of Surgeons in Ireland, Dublin 2, Ireland – sequence: 14 givenname: Luise surname: Halang fullname: Halang, Luise organization: Department of Physiology and Medical Physics, Royal College of Surgeons in Ireland, Dublin 2, Ireland – sequence: 15 givenname: Marion surname: Hogg fullname: Hogg, Marion organization: Department of Biosciences, Nottingham Trent University, Clifton Campus, Nottingham, UK – sequence: 16 givenname: Amaya Garcia surname: Muñoz fullname: Muñoz, Amaya Garcia organization: Systems Biology Ireland, School of Medicine, University College Dublin, Dublin 4, Belfield, Ireland – sequence: 17 givenname: Eugène T surname: Dillon fullname: Dillon, Eugène T organization: Mass Spectrometry Resource, Conway Institute of Biomolecular & Biomedical Research, University College Dublin, Dublin 4, Ireland – sequence: 18 givenname: David surname: Matallanas fullname: Matallanas, David organization: Systems Biology Ireland, School of Medicine, University College Dublin, Dublin 4, Belfield, Ireland – sequence: 19 givenname: Ingrid surname: Arijs fullname: Arijs, Ingrid organization: VIB Center for Cancer Biology, Leuven, Belgium – sequence: 20 givenname: Diether surname: Lambrechts fullname: Lambrechts, Diether organization: VIB Center for Cancer Biology, Leuven, Belgium – sequence: 21 givenname: Daniele surname: Bano fullname: Bano, Daniele organization: German Center for Neurodegenerative Diseases (DZNE), Bonn, Germany – sequence: 22 givenname: Niamh M C surname: Connolly fullname: Connolly, Niamh M C organization: Department of Physiology and Medical Physics, Royal College of Surgeons in Ireland, Dublin 2, Ireland – sequence: 23 givenname: Jochen H M orcidid: 0000-0003-3479-7794 surname: Prehn fullname: Prehn, Jochen H M organization: SFI FutureNeuro Research Centre, Dublin 2, Ireland |
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Keywords | frontotemporal dementia (FTD) master regulator analysis mitochondrial dysfunction Amyotrophic lateral sclerosis (ALS) bioinformatics lipid metabolism |
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SubjectTerms | Amyotrophic Lateral Sclerosis - pathology Animals Frontotemporal Dementia - metabolism Gene Expression Profiling Humans Mice Mice, Transgenic Mitochondrial Diseases Neurodegenerative Diseases Pick Disease of the Brain Proteomics RNA, Messenger |
Title | Integrated analysis of transcriptomic and proteomic alterations in mouse models of ALS/FTD identify early metabolic adaptions with similarities to mitochondrial dysfunction disorders |
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