Mouse exhibits a range of HSP characteristics
A multinational team led by researchers from the National Institute for Neurological Disorders and Stroke (NINDS) in the USA have developed a unique HSP mouse that shows promise for testing potential therapies to treat HSPs.
The mouse exhibits early-onset and rapidly progressive decline in walking. It also shows HSP type changes in axonal structures and composition in the corticospinal neurons.
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, while 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, based on 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.
SOURCE: Hum Mol Genet. 2022 Mar 26;ddac072. doi: 10.1093/hmg/ddac072. Online ahead of print. PMID: 35348668 © The Author(s) 2022.
Transverse endoplasmic reticulum expansion in hereditary spastic paraplegia corticospinal axons
Peng-Peng Zhu 1 , Hui-Fang Hung 1 2 3 , Natalia Batchenkova 1 , Jonathon Nixon-Abell 1 4 5 , James Henderson 5 , Pengli Zheng 1 2 3 , Benoit Renvoisé 1 , Song Pang 4 , C Shan Xu 4 , Stephan Saalfeld 4 , Jan Funke 4 , Yuxiang Xie 6 , Fabian Svara 7 8 , Harald F Hess 4 , Craig Blackstone 1 2 3
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.