Transverse endoplasmic reticulum expansion in hereditary spastic paraplegia corticospinal axons

Author:

Zhu Peng-Peng1,Hung Hui-Fang123,Batchenkova Natalia1,Nixon-Abell Jonathon145,Henderson James5,Zheng Pengli123,Renvoisé Benoit1,Pang Song4,Xu C Shan4,Saalfeld Stephan4,Funke Jan4,Xie Yuxiang6,Svara Fabian78,Hess Harald F4,Blackstone Craig123ORCID

Affiliation:

1. Neurogenetics Branch , National Institute of Neurological Disorders and Stroke, National Institutes of Health, Bethesda, MD 20892, USA

2. MassGeneral Institute for Neurodegenerative Disease , Charlestown, MA 02129, USA

3. Department of Neurology , Massachusetts General Hospital and Harvard Medical School, Boston, MA 02114, USA

4. Howard Hughes Medical Institute , Janelia Research Campus, Ashburn, VA 20147, USA

5. Cambridge Institute for Medical Research , Cambridge CB2 0XY, UK

6. Synaptic Function Section , National Institute of Neurological Disorders and Stroke, National Institutes of Health, Bethesda, MD 20892, USA

7. ariadne.ai ag , CH-6033 Buchrain, Switzerland

8. Research Center Caesar , D-53175 Bonn, Germany

Abstract

Abstract Hereditary spastic paraplegias (HSPs) comprise a large group of inherited neurologic disorders affecting the longest corticospinal axons (SPG1–86 plus others), with shared manifestations of lower extremity spasticity and gait impairment. Common autosomal dominant HSPs are caused by mutations in genes encoding the microtubule-severing ATPase spastin (SPAST; SPG4), the membrane-bound GTPase atlastin-1 (ATL1; SPG3A) and the reticulon-like, microtubule-binding protein REEP1 (REEP1; SPG31). These proteins bind one another and function in shaping the tubular endoplasmic reticulum (ER) network. Typically, mouse models of HSPs have mild, later onset phenotypes, possibly reflecting far shorter lengths of their corticospinal axons relative to humans. Here, we have generated a robust, double mutant mouse model of HSP in which atlastin-1 is genetically modified with a K80A knock-in (KI) missense change that abolishes its GTPase activity, whereas its binding partner Reep1 is knocked out. Atl1KI/KI/Reep1−/− mice exhibit early onset and rapidly progressive declines in several motor function tests. Also, ER in mutant corticospinal axons dramatically expands transversely and periodically in a mutation dosage-dependent manner to create a ladder-like appearance, on the basis of reconstructions of focused ion beam-scanning electron microscopy datasets using machine learning-based auto-segmentation. In lockstep with changes in ER morphology, axonal mitochondria are fragmented and proportions of hypophosphorylated neurofilament H and M subunits are dramatically increased in Atl1KI/KI/Reep1−/− spinal cord. Co-occurrence of these findings links ER morphology changes to alterations in mitochondrial morphology and cytoskeletal organization. Atl1KI/KI/Reep1−/− mice represent an early onset rodent HSP model with robust behavioral and cellular readouts for testing novel therapies.

Funder

Howard Hughes Medical Institute

National Institutes of Health

Publisher

Oxford University Press (OUP)

Subject

Genetics (clinical),Genetics,Molecular Biology,General Medicine

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