Integrated genomic, proteomic and cognitive assessment in Duchenne Muscular Dystrophy suggest astrocyte centric pathology
Introduction: Documented Duchenne Muscular Dystrophy (DMD) biomarkers are confined to Caucasians and are poor indicators of cognitive difficulties and neuropsychological alterations. Materials and methods: This study correlates serum protein signatures with cognitive performance in DMD patients of S...
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| Format: | Article |
| Language: | English |
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Elsevier
2023-08-01
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| Series: | Heliyon |
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| Online Access: | http://www.sciencedirect.com/science/article/pii/S2405844023057389 |
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| author | Nalaka Wijekoon Lakmal Gonawala Pyara Ratnayake Pulasthi Dissanayaka Isuru Gunarathne Dhammika Amaratunga Roshan Liyanage Sunethra Senanayaka Saraji Wijesekara Hemal H. Gunasekara Kamala Vanarsa Jessica Castillo Yetrib Hathout Ashwin Dalal Harry W.M. Steinbusch Eric Hoffman Chandra Mohan K. Ranil D. de Silva |
| author_facet | Nalaka Wijekoon Lakmal Gonawala Pyara Ratnayake Pulasthi Dissanayaka Isuru Gunarathne Dhammika Amaratunga Roshan Liyanage Sunethra Senanayaka Saraji Wijesekara Hemal H. Gunasekara Kamala Vanarsa Jessica Castillo Yetrib Hathout Ashwin Dalal Harry W.M. Steinbusch Eric Hoffman Chandra Mohan K. Ranil D. de Silva |
| author_sort | Nalaka Wijekoon |
| collection | DOAJ |
| description | Introduction: Documented Duchenne Muscular Dystrophy (DMD) biomarkers are confined to Caucasians and are poor indicators of cognitive difficulties and neuropsychological alterations. Materials and methods: This study correlates serum protein signatures with cognitive performance in DMD patients of South Asian origin. Study included 25 DMD patients aged 6–16 years. Cognitive profiles were assessed by Wechsler Intelligence Scale for Children. Serum proteome profiling of 1317 proteins was performed in eight DMD patients and eight age-matched healthy volunteers. Results: Among the several novel observations we report, better cognitive performance in DMD was associated with increased serum levels of MMP9 and FN1 but decreased Siglec-3, C4b, and C3b. Worse cognitive performance was associated with increased serum levels of LDH-H1 and PDGF-BB but reduced GDF-11, MMP12, TPSB2, and G1B. Secondly, better cognitive performance in Processing Speed (PSI) and Perceptual Reasoning (PRI) domains was associated with intact Dp116, Dp140, and Dp71 dystrophin isoforms while better performance in Verbal Comprehension (VCI) and Working Memory (WMI) domains was associated with intact Dp116 and Dp140 isoforms. Finally, functional pathways shared with Alzheimer's Disease (AD) point towards an astrocyte-centric model for DMD. Conclusion: Astrocytic dysfunction leading to synaptic dysfunction reported previously in AD may be a common pathogenic mechanism underlying both AD and DMD, linking protein alterations to cognitive impairment. This new insight may pave the path towards novel therapeutic approaches targeting reactive astrocytes. |
| first_indexed | 2024-03-12T12:23:10Z |
| format | Article |
| id | doaj.art-ea7f989c48ed46f8ad872ba9e802e1d3 |
| institution | Directory Open Access Journal |
| issn | 2405-8440 |
| language | English |
| last_indexed | 2024-03-12T12:23:10Z |
| publishDate | 2023-08-01 |
| publisher | Elsevier |
| record_format | Article |
| series | Heliyon |
| spelling | doaj.art-ea7f989c48ed46f8ad872ba9e802e1d32023-08-30T05:51:38ZengElsevierHeliyon2405-84402023-08-0198e18530Integrated genomic, proteomic and cognitive assessment in Duchenne Muscular Dystrophy suggest astrocyte centric pathologyNalaka Wijekoon0Lakmal Gonawala1Pyara Ratnayake2Pulasthi Dissanayaka3Isuru Gunarathne4Dhammika Amaratunga5Roshan Liyanage6Sunethra Senanayaka7Saraji Wijesekara8Hemal H. Gunasekara9Kamala Vanarsa10Jessica Castillo11Yetrib Hathout12Ashwin Dalal13Harry W.M. Steinbusch14Eric Hoffman15Chandra Mohan16K. Ranil D. de Silva17Interdisciplinary Center for Innovation in Biotechnology and Neuroscience, Faculty of Medical Sciences, University of Sri Jayewardenepura, Nugegoda, 10250, Sri Lanka; Department of Cellular and Translational Neuroscience, School for Mental Health and Neuroscience, Faculty of Health, Medicine & Life Sciences, Maastricht University, Maastricht, The NetherlandsInterdisciplinary Center for Innovation in Biotechnology and Neuroscience, Faculty of Medical Sciences, University of Sri Jayewardenepura, Nugegoda, 10250, Sri Lanka; Department of Cellular and Translational Neuroscience, School for Mental Health and Neuroscience, Faculty of Health, Medicine & Life Sciences, Maastricht University, Maastricht, The NetherlandsLady Ridgway Children’s Hospital, 00800, Sri LankaInterdisciplinary Center for Innovation in Biotechnology and Neuroscience, Faculty of Medical Sciences, University of Sri Jayewardenepura, Nugegoda, 10250, Sri LankaInterdisciplinary Center for Innovation in Biotechnology and Neuroscience, Faculty of Medical Sciences, University of Sri Jayewardenepura, Nugegoda, 10250, Sri LankaPrinceton Data Analytics, 08544, USAInterdisciplinary Center for Innovation in Biotechnology and Neuroscience, Faculty of Medical Sciences, University of Sri Jayewardenepura, Nugegoda, 10250, Sri LankaNational Hospital, 00700, Sri LankaDepartment of Pediatrics, University of Sri Jayewardenepura, 10250, Sri Lanka; Colombo South Teaching Hospital, 10350, Sri LankaSri Jayewardenepura General Hospital, 10250, Sri LankaDepartment of Bioengineering, University of Houston, Houston, 77204, USADepartment of Bioengineering, University of Houston, Houston, 77204, USASchool of Pharmacy and Pharmaceutical Sciences, Binghamton University, New York, USADiagnostics Division, Center for DNA Fingerprinting and Diagnostics, IndiaDepartment of Cellular and Translational Neuroscience, School for Mental Health and Neuroscience, Faculty of Health, Medicine & Life Sciences, Maastricht University, Maastricht, The NetherlandsSchool of Pharmacy and Pharmaceutical Sciences, Binghamton University, New York, USADepartment of Bioengineering, University of Houston, Houston, 77204, USAInterdisciplinary Center for Innovation in Biotechnology and Neuroscience, Faculty of Medical Sciences, University of Sri Jayewardenepura, Nugegoda, 10250, Sri Lanka; Department of Cellular and Translational Neuroscience, School for Mental Health and Neuroscience, Faculty of Health, Medicine & Life Sciences, Maastricht University, Maastricht, The Netherlands; Institute for Combinatorial Advanced Research and Education (KDU-CARE), General Sir John Kotelawala Defence University, Ratmalana, 10390, Sri Lanka; Corresponding author. Interdisciplinary Center for Innovation in Biotechnology and Neuroscience, Faculty of Medical Sciences, University of Sri Jayewardenepura, Nugegoda, 10250, Sri Lanka.Introduction: Documented Duchenne Muscular Dystrophy (DMD) biomarkers are confined to Caucasians and are poor indicators of cognitive difficulties and neuropsychological alterations. Materials and methods: This study correlates serum protein signatures with cognitive performance in DMD patients of South Asian origin. Study included 25 DMD patients aged 6–16 years. Cognitive profiles were assessed by Wechsler Intelligence Scale for Children. Serum proteome profiling of 1317 proteins was performed in eight DMD patients and eight age-matched healthy volunteers. Results: Among the several novel observations we report, better cognitive performance in DMD was associated with increased serum levels of MMP9 and FN1 but decreased Siglec-3, C4b, and C3b. Worse cognitive performance was associated with increased serum levels of LDH-H1 and PDGF-BB but reduced GDF-11, MMP12, TPSB2, and G1B. Secondly, better cognitive performance in Processing Speed (PSI) and Perceptual Reasoning (PRI) domains was associated with intact Dp116, Dp140, and Dp71 dystrophin isoforms while better performance in Verbal Comprehension (VCI) and Working Memory (WMI) domains was associated with intact Dp116 and Dp140 isoforms. Finally, functional pathways shared with Alzheimer's Disease (AD) point towards an astrocyte-centric model for DMD. Conclusion: Astrocytic dysfunction leading to synaptic dysfunction reported previously in AD may be a common pathogenic mechanism underlying both AD and DMD, linking protein alterations to cognitive impairment. This new insight may pave the path towards novel therapeutic approaches targeting reactive astrocytes.http://www.sciencedirect.com/science/article/pii/S2405844023057389Brain regionsIntelligenceMemoryDp71Dp140Alzheimer’s disease |
| spellingShingle | Nalaka Wijekoon Lakmal Gonawala Pyara Ratnayake Pulasthi Dissanayaka Isuru Gunarathne Dhammika Amaratunga Roshan Liyanage Sunethra Senanayaka Saraji Wijesekara Hemal H. Gunasekara Kamala Vanarsa Jessica Castillo Yetrib Hathout Ashwin Dalal Harry W.M. Steinbusch Eric Hoffman Chandra Mohan K. Ranil D. de Silva Integrated genomic, proteomic and cognitive assessment in Duchenne Muscular Dystrophy suggest astrocyte centric pathology Heliyon Brain regions Intelligence Memory Dp71 Dp140 Alzheimer’s disease |
| title | Integrated genomic, proteomic and cognitive assessment in Duchenne Muscular Dystrophy suggest astrocyte centric pathology |
| title_full | Integrated genomic, proteomic and cognitive assessment in Duchenne Muscular Dystrophy suggest astrocyte centric pathology |
| title_fullStr | Integrated genomic, proteomic and cognitive assessment in Duchenne Muscular Dystrophy suggest astrocyte centric pathology |
| title_full_unstemmed | Integrated genomic, proteomic and cognitive assessment in Duchenne Muscular Dystrophy suggest astrocyte centric pathology |
| title_short | Integrated genomic, proteomic and cognitive assessment in Duchenne Muscular Dystrophy suggest astrocyte centric pathology |
| title_sort | integrated genomic proteomic and cognitive assessment in duchenne muscular dystrophy suggest astrocyte centric pathology |
| topic | Brain regions Intelligence Memory Dp71 Dp140 Alzheimer’s disease |
| url | http://www.sciencedirect.com/science/article/pii/S2405844023057389 |
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