Integrated genomic, proteomic and cognitive assessment in Duchenne Muscular Dystrophy suggest astrocyte centric pathology

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

doi:10.1016/j.heliyon.2023.e18530

Integrated genomic, proteomic and cognitive assessment in Duchenne Muscular Dystrophy suggest astrocyte centric pathology

Heliyon. 2023 Jul 25;9(8):e18530. doi: 10.1016/j.heliyon.2023.e18530. eCollection 2023 Aug.

Authors

Nalaka Wijekoon^{1

2}, Lakmal Gonawala^{1

2}, Pyara Ratnayake³, Pulasthi Dissanayaka¹, Isuru Gunarathne¹, Dhammika Amaratunga⁴, Roshan Liyanage¹, Sunethra Senanayaka⁵, Saraji Wijesekara^{6

7}, Hemal H Gunasekara⁸, Kamala Vanarsa⁹, Jessica Castillo⁹, Yetrib Hathout¹⁰, Ashwin Dalal¹¹, Harry W M Steinbusch², Eric Hoffman¹⁰, Chandra Mohan⁹, K Ranil D de Silva^{1

2

12}

Affiliations

¹ Interdisciplinary Center for Innovation in Biotechnology and Neuroscience, Faculty of Medical Sciences, University of Sri Jayewardenepura, Nugegoda, 10250, Sri Lanka.
² Department of Cellular and Translational Neuroscience, School for Mental Health and Neuroscience, Faculty of Health, Medicine & Life Sciences, Maastricht University, Maastricht, The Netherlands.
³ Lady Ridgway Children's Hospital, 00800, Sri Lanka.
⁴ Princeton Data Analytics, 08544, USA.
⁵ National Hospital, 00700, Sri Lanka.
⁶ Department of Pediatrics, University of Sri Jayewardenepura, 10250, Sri Lanka.
⁷ Colombo South Teaching Hospital, 10350, Sri Lanka.
⁸ Sri Jayewardenepura General Hospital, 10250, Sri Lanka.
⁹ Department of Bioengineering, University of Houston, Houston, 77204, USA.
¹⁰ School of Pharmacy and Pharmaceutical Sciences, Binghamton University, New York, USA.
¹¹ Diagnostics Division, Center for DNA Fingerprinting and Diagnostics, India.
¹² Institute for Combinatorial Advanced Research and Education (KDU-CARE), General Sir John Kotelawala Defence University, Ratmalana, 10390, Sri Lanka.

Abstract

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.

Keywords: Alzheimer’s disease; Brain regions; Dp140; Dp71; Intelligence; Memory.