Transverse endoplasmic reticulum expansion in hereditary spastic paraplegia corticospinal axons.
Peng-Peng ZhuHui-Fang HungNatalia BatchenkovaJonathon Nixon-AbellJames HendersonPengli ZhengBenoit RenvoiséSong PangC Shan XuStephan SaalfeldJan FunkeYuxiang XieFabian SvaraHarald F HessCraig BlackstonePublished in: Human molecular genetics (2022)
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.
Keyphrases
- endoplasmic reticulum
- early onset
- heat shock
- neoadjuvant chemotherapy
- mouse model
- electron microscopy
- late onset
- spinal cord
- spinal cord injury
- cerebral palsy
- binding protein
- transcranial magnetic stimulation
- botulinum toxin
- heat shock protein
- wild type
- deep learning
- gene expression
- magnetic resonance
- type diabetes
- cell death
- adipose tissue
- mass spectrometry
- transcription factor
- endothelial cells
- magnetic resonance imaging
- hiv infected
- estrogen receptor
- optical coherence tomography
- lymph node
- intellectual disability
- neuropathic pain