Approved statins may help fix the problem
The lack of AMFR protein leading to lipid droplet accumulation in SPG89 was corrected by returning the protein levels to normal in cultured skin cell samples from an SPG89 cohort, which together with zebrafish larvae were used to investigate the disease mechanism.
Statins currently approved for human use improved impairments in zebrafish larvae with a lack of AMFR protein.
A huge multinational collaboration between researchers is behind the significant and successful outcomes achieved from the study. 20 individuals from 8 unrelated consanguineous families were identified with SPG89 in both pure and complex forms.
Hereditary spastic paraplegias (HSP) are rare, inherited neurodegenerative or neurodevelopmental disorders that mainly present with lower limb spasticity and muscle weakness due to motor neuron dysfunction.
Whole genome sequencing identified bi-allelic truncating variants in AMFR, encoding a RING-H2 finger E3 ubiquitin ligase anchored at the membrane of the endoplasmic reticulum (ER), in two previously genetically unexplained HSP-affected siblings. Subsequently, international collaboration recognized additional HSP-affected individuals with similar bi-allelic truncating AMFR variants, resulting in a cohort of 20 individuals from 8 unrelated, consanguineous families.
Variants segregated with a phenotype of mainly pure but also complex HSP consisting of global developmental delay, mild intellectual disability, motor dysfunction, and progressive spasticity. Patient-derived fibroblasts, neural stem cells (NSCs), and in vivo zebrafish modeling were used to investigate pathomechanisms, including initial preclinical therapy assessment.
The absence of AMFR disturbs lipid homeostasis, causing lipid droplet accumulation in NSCs and patient-derived fibroblasts which is rescued upon AMFR re-expression. Electron microscopy indicates ER morphology alterations in the absence of AMFR. Similar findings are seen in amfra-/- zebrafish larvae, in addition to altered touch-evoked escape response and defects in motor neuron branching, phenocopying the HSP observed in patients. Interestingly, administration of FDA-approved statins improves touch-evoked escape response and motor neuron branching defects in amfra-/- zebrafish larvae, suggesting potential therapeutic implications.
Our genetic and functional studies identify bi-allelic truncating variants in AMFR as a cause of a novel autosomal recessive HSP by altering lipid metabolism, which may potentially be therapeutically modulated using precision medicine with statins.
SOURCE: Acta Neuropathol. 2023 Aug;146(2):353-368.
doi: 10.1007/s00401-023-02579-9. Epub 2023 Apr 29. PMID: 37119330 © 2023. The Author(s).
AMFR dysfunction causes autosomal recessive spastic paraplegia in human that is amenable to statin treatment in a preclinical model
Ruizhi Deng # 1 2 , Eva Medico-Salsench 1 , Anita Nikoncuk 1 , Reshmi Ramakrishnan 3 , Kristina Lanko 1 , Nikolas A Kühn 4 , Herma C van der Linde 1 , Sarah Lor-Zade 1 , Fatimah Albuainain 1 , Yuwei Shi 1 , Soheil Yousefi 1 2 , Ivan Capo 5 , Evita Medici van den Herik 6 , Marjon van Slegtenhorst 1 , Rick van Minkelen 1 , Geert Geeven 1 2 , Monique T Mulder 7 , George J G Ruijter 1 , Dieter Lütjohann 8 , Edwin H Jacobs 1 , Henry Houlden 9 , Alistair T Pagnamenta 10 , Kay Metcalfe 11 12 , Adam Jackson 11 12 , Siddharth Banka 11 12 , Lenika De Simone 13 , Abigail Schwaede 13 , Nancy Kuntz 13 , Timothy Blake Palculict 14 , Safdar Abbas 15 , Muhammad Umair 16 17 , Mohammed AlMuhaizea 18 , Dilek Colak 19 , Hanan AlQudairy 20 , Maysoon Alsagob 20 21 , Catarina Pereira 22 , Roberta Trunzo 22 , Vasiliki Karageorgou 22 , Aida M Bertoli-Avella 22 , Peter Bauer 22 , Arjan Bouman 1 , Lies H Hoefsloot 1 2 , Tjakko J van Ham 1 2 , Mahmoud Issa 23 , Maha S Zaki 23 , Joseph G Gleeson 24 , Rob Willemsen 1 , Namik Kaya 20 , Stefan T Arold 3 25 , Reza Maroofian 9 , Leslie E Sanderson 1 , Tahsin Stefan Barakat 26 27 28 29
1. Department of Clinical Genetics, Erasmus MC University Medical Center, Rotterdam, The Netherlands.
2. Whole Genome Sequencing Implementation and Research Task Force, Department of Clinical Genetics, Erasmus MC University Medical Center, Rotterdam, The Netherlands.
3. Bioscience Program, Biological and Environmental Science and Engineering Division, Computational Bioscience Research Center, King Abdullah University of Science and Technology (KAUST), Thuwal, 23955-6900, Saudi Arabia.
4. Department of Cell Biology, Erasmus MC University Medical Center, Rotterdam, The Netherlands.
5. Department for Histology and Embryology, Faculty of Medicine, University of Novi Sad, Novi Sad, Serbia.
6. Department of Neurology, Erasmus MC University Medical Center, Rotterdam, The Netherlands.
7. Department of Internal Medicine, Erasmus MC University Medical Center, Rotterdam, The Netherlands.
8. Institute of Clinical Chemistry and Clinical Pharmacology, University Hospital Bonn, Bonn, Germany.
9. Department of Neuromuscular Disorders, UCL Queen Square Institute of Neurology, London, UK.
10. NIHR Biomedical Research Centre, Wellcome Centre for Human Genetics, University of Oxford, Oxford, UK.
11. Manchester Centre for Genomic Medicine, St Mary’s Hospital, Health Innovation Manchester, Manchester University Foundation NHS Trust, Manchester, UK.
12. Division of Evolution, Infection and Genomics, School of Biological Sciences, Faculty of Biology, Medicine and Health, The University of Manchester, Manchester, M13 9PL, UK.
13. Division of Neurology, Division of Genetics, Ann & Robert H. Lurie Children’s Hospital of Chicago, Chicago, USA.
14. GeneDx, Gaithersburg, MD, 20877, USA.
15. Department of Biological Science, Dartmouth College, Hanover, NH, USA.
16. Medical Genomics Research Department, King Abdullah International Medical Research Center (KAIMRC), King Saud Bin Abdulaziz University for Health Sciences, Ministry of National Guard Health Affairs, Riyadh, Saudi Arabia.
17. Department of Life Sciences, School of Science, University of Management and Technology (UMT), Lahore, Pakistan.
18. Neuroscience Centre, King Faisal Specialist Hospital and Research Centre (KFSHRC), MBC: 76, Riyadh, 11211, Saudi Arabia.
19. Molecular Oncology Department, King Faisal Specialist Hospital and Research Centre (KFSHRC), MBC: 03, Riyadh, 11211, Saudi Arabia.
20. Translational Genomics Department, Center for Genomics Medicine, King Faisal Specialist Hospital and Research Centre, MBC: 26, PO Box: 3354, Riyadh, 11211, Saudi Arabia.
21. Applied Genomics Technologies Institute, King Abdulaziz City for Science and Technology (KACST), Riyadh, Saudi Arabia.
22. CENTOGENE, GmbH, 18055, Rostock, Germany.
23. Clinical Genetics Department, Human Genetics and Genome Research Institute, National Research Centre, Cairo, Egypt.
24. Departments of Neurosciences and Pediatrics, Howard Hughes Medical Institute, University of California, Rady Children’s Institute for Genomic Medicine, San Diego, USA.
25. Centre de Biologie Structurale, CNRS, INSERM, Université de Montpellier, 34090, Montpellier, France.
26. Department of Clinical Genetics, Erasmus MC University Medical Center, Rotterdam, The Netherlands.
27. Whole Genome Sequencing Implementation and Research Task Force, Department of Clinical Genetics, Erasmus MC University Medical Center, Rotterdam, The Netherlands.
28. ENCORE Expertise Center for Neurodevelopmental Disorders, Erasmus MC University Medical Center, Rotterdam, The Netherlands.
29. Discovery Unit, Department of Clinical Genetics, Erasmus MC University Medical Center, Rotterdam, The Netherlands.
# Contributed equally.