Hereditary spastic paraplegias (HSPs) are neurodegenerative diseases caused by mutations in more than 20 genes, which lead to progressive spasticity and weakness of the lower limbs. The most frequently mutated gene causing autosomal dominant HSP is SPG4, which encodes spastin, a protein that belongs to the family of ATPases associated with various cellular activities (AAAs). A number of studies have suggested that spastin regulates microtubule dynamics. We have studied the ATPase activity of recombinant human spastin and examined the effect of taxol-stabilized microtubules on this activity. We used spastin translated from the second ATG and provide evidence that this is the physiologically relevant form. We showed that microtubules enhance the ATPase activity of the protein, a property also described for katanin, an AAA of the same spastin subgroup. Furthermore, we demonstrated that human spastin has a microtubule-destabilizing activity and can bundle microtubules in vitro, providing new insights into the molecular pathogenesis of HSP.
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From spastic paraplegia to infantile neurodegenerative disorder: Expanding the phenotypic spectrum associated with biallelic SPAST variants.
Eur J Neurol
January 2025
Service de Génétique Médicale, CHU Bordeaux, Bordeaux, France.
Purpose: Heterozygous pathogenic variants in SPAST are known to cause Hereditary Spastic Paraplegia 4 (SPG4), the most common form of HSP, characterized by progressive bilateral lower limbs spasticity with frequent sphincter disorders. However, there are very few descriptions in the literature of patients carrying biallelic variants in SPAST.
Methods: Targeted Sanger sequencing, panel sequencing and exome sequencing were used to identify the genetic causes in 9 patients from 6 unrelated families with symptoms of HSP or infantile neurodegenerative disorder.
Fidgetin binds spastin to attenuate the microtubule-severing activity.
Biochim Biophys Acta Mol Cell Res
February 2025
Key Laboratory of Neuroregeneration of Jiangsu and Ministry of Education, Co-innovation Center of Neuroregeneration, Nantong University, Nantong, Jiangsu 226001, China. Electronic address:
Microtubule-severing enzymes such as spastin, katanin, and fidgetin, characterized by their AAA ATPase domains, are pivotal in modulating microtubule dynamics and behavior across various cellular processes. While spastin and katanin are recognized for their predominant and robust severing of stable microtubules, thereby enhancing microtubule turnover, fidgetin exhibits comparatively weaker severing activity and selectively targets labile microtubules. The interplay among these enzymes and their mutual regulatory mechanisms remains inadequately understood.
View Article and Find Full Text PDF[Successful application of preimplantation genetic testing combined with thirdgeneration sequencing for blocking hereditary spastic paraplegia].
Nan Fang Yi Ke Da Xue Xue Bao
November 2024
Department of Reproductive Medicine, Jinling Clinical Medical College, Nanjing University of Chinese Medicine, Nanjng 210002, China.
Article Synopsis
- A family with hereditary spastic paraplegia (HSP) due to mutations in the SPAST gene underwent third-generation sequencing (TGS) and preimplantation genetic testing (PGT) to prevent passing the condition to their children.
- They identified a specific mutation in the SPAST gene and used advanced genetic testing during in vitro fertilization to select embryos free of the mutation.
- The successful process resulted in the birth of a healthy baby girl, demonstrating that TGS and PGT-M are effective methods for managing hereditary diseases and ensuring the health of offspring.
Spastin accumulation and motor neuron defects caused by a novel SPAST splice site mutation.
J Transl Med
September 2024
Department of Neurology, Peking Union Medical College, Peking Union Medical College Hospital, Chinese Academy of Medical Science, Beijing, 100730, China.
Article Synopsis
- Hereditary spastic paraplegia (HSP) is a rare disorder primarily caused by mutations in the SPAST gene, with a complex pathogenic mechanism that isn't fully understood.
- Researchers investigated a Chinese family to identify the causative gene of autosomal dominant HSP-SPAST and discovered a novel splice site variant that affects gene expression.
- Experiments showed that this mutation leads to a truncated protein causing cellular accumulation and resulting in significant developmental issues in zebrafish, including defects in motor neuron pathfinding and axon loss.
Microtubule-associated protein, MAP1B, encodes functionally distinct polypeptides.
J Biol Chem
November 2024
Department of Molecular and Cellular Biology, University of California, Davis, California, USA. Electronic address:
Microtubule-associated protein, MAP1B, is crucial for neuronal morphogenesis and disruptions in MAP1B function are correlated with neurodevelopmental disorders. MAP1B encodes a single polypeptide that is processed into discrete proteins, a heavy chain (HC) and a light chain (LC); however, it is unclear if these two chains operate individually or as a complex within the cell. In vivo studies have characterized the contribution of MAP1B HC and LC to microtubule and actin-based processes, but their molecular mechanisms of action are unknown.
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