ArticleHuman molecular genetics2019
Hereditary spastic paraplegia: gain-of-function mechanisms revealed by new transgenic mouse.
Article in Human molecular genetics, 2019. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 25 papers, 1 of them a synthesis that pooled it.
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Who cites it
25 citing papers in PubMed, 1 synthesis or guideline pooled it, 34 citations in OpenAlex.
- Pooled it
- Proteomic analysis reveals early pathological defects in corticospinal motor neurons of a spastin model of hereditary spastic paraplegia, which are improved by NU-9 treatment.Neurobiology of disease · 2026Article
- A GJA1 Variant Triggers Earlier SPG4 Onset by Destabilizing Deubiquitinase VCPIP1 to Lower SPASTIN Levels.Movement disorders : official journal of the Movement Disorder Society · 2026Article
- Modeling spastic paraplegia 4 with corticospinal motor neuron-enriched cortical organoids reveals genotype-phenotype and HDAC6-targetable pathology.Cell reports · 2026Article
- Expanding Hereditary Spastic Paraplegias Limits: Biallelic SPAST Variants in Cerebral Palsy Mimics.Annals of clinical and translational neurology · 2026Article
- Unraveling Isoform Complexity: The Roles of M1- and M87-Spastin in Spastic Paraplegia 4 (SPG4).Movement disorders : official journal of the Movement Disorder Society · 2025Review
- Tail Anchored protein insertion mediated by CAML and TRC40 links to neuromuscular function in mice.PLoS genetics · 2025Article
- Development and validation a novel FEZF2 based fluorescent reporter for corticospinal motor neurons.Metabolic brain disease · 2024Article
- Spastin accumulation and motor neuron defects caused by a novel SPAST splice site mutation.Journal of translational medicine · 2024Article
- A noveleNeurologicalSci · 2024Article
- Conditional Astrocyte Rac1KO Attenuates Hyperreflexia after Spinal Cord Injury.The Journal of neuroscience : the official journal of the Society for Neuroscience · 2024Article
- Deletion of Transferrin Receptor 1 in Parvalbumin Interneurons Induces a Hereditary Spastic Paraplegia-Like Phenotype.The Journal of neuroscience : the official journal of the Society for Neuroscience · 2023Article
- A novel missense mutation inMolecular medicine reports · 2023Article
- Spastin is an essential regulator of male meiosis, acrosome formation, manchette structure and nuclear integrity.Development (Cambridge, England) · 2023Article
- Ubap1 knock-in mice reproduced the phenotype of SPG80.Journal of human genetics · 2022Article
- TFG regulates secretory and endosomal sorting pathways in neurons to promote their activity and maintenance.Proceedings of the National Academy of Sciences of the United States of America · 2022Article
- Modeling gain-of-function and loss-of-function components of SPAST-based hereditary spastic paraplegia using transgenic mice.Human molecular genetics · 2022Article
- A Novel SPAST Mutation Results in Spastin Accumulation and Defects in Microtubule Dynamics.Movement disorders : official journal of the Movement Disorder Society · 2022Article
- The Role of Spastin in Axon Biology.Frontiers in cell and developmental biology · 2022Review
- Molecular and cellular mechanisms of spastin in neural development and disease (Review).International journal of molecular medicine · 2021Review
Corrections and comments
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Authors and funding
16 authors at 2 institutions in 1 country.
Funding
Abstract
Mutations of the SPAST gene, which encodes the microtubule-severing protein spastin, are the most common cause of hereditary spastic paraplegia (HSP). Haploinsufficiency is the prevalent opinion as to the mechanism of the disease, but gain-of-function toxicity of the mutant proteins is another possibility. Here, we report a new transgenic mouse (termed SPASTC448Y mouse) that is not haploinsufficient but expresses human spastin bearing the HSP pathogenic C448Y mutation. Expression of the mutant spastin was documented from fetus to adult, but gait defects reminiscent of HSP (not observed in spastin knockout mice) were adult onset, as is typical of human patients. Results of histological and tracer studies on the mouse are consistent with progressive dying back of corticospinal axons, which is characteristic of the disease. The C448Y-mutated spastin alters microtubule stability in a manner that is opposite to the expectations of haploinsufficiency. Neurons cultured from the mouse display deficits in organelle transport typical of axonal degenerative diseases, and these deficits were worsened by depletion of endogenous mouse spastin. These results on the SPASTC448Y mouse are consistent with a gain-of-function mechanism underlying HSP, with spastin haploinsufficiency exacerbating the toxicity of the mutant spastin proteins. These findings reveal the need for a different therapeutic approach than indicated by haploinsufficiency alone.
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