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1.
Int J Mol Med ; 48(6)2021 Dec.
Artigo em Inglês | MEDLINE | ID: mdl-34664680

RESUMO

Spastin is a microtubule (MT)­severing enzyme identified from mutations of hereditary spastic paraplegia in 1999 and extensive studies indicate its vital role in various cellular activities. In the past two decades, efforts have been made to understand the underlying molecular mechanisms of how spastin is linked to neural development and disease. Recent studies on spastin have unraveled the mechanistic processes of its MT­severing activity and revealed that spastin acts as an MT amplifier to mediate its remodeling, thus providing valuable insight into the molecular roles of spastin under physiological conditions. In addition, recent research has revealed multiple novel molecular mechanisms of spastin in cellular biological pathways, including endoplasmic reticulum shaping, calcium trafficking, fatty acid trafficking, as well as endosomal fission and trafficking. These processes are closely involved in axonal and dendritic development and maintenance. The current review presents recent biological advances regarding the molecular mechanisms of spastin at the cellular level and provides insight into how it affects neural development and disease.


Assuntos
Neurogênese/fisiologia , Paraplegia/etiologia , Espastina/fisiologia , Animais , Axônios/fisiologia , Complexos Endossomais de Distribuição Requeridos para Transporte/química , Complexos Endossomais de Distribuição Requeridos para Transporte/metabolismo , Humanos , Domínios Proteicos , Espastina/química
2.
Life Sci Alliance ; 3(12)2020 12.
Artigo em Inglês | MEDLINE | ID: mdl-33106322

RESUMO

Hereditary Spastic Paraplegia (HSP) is a neurodegenerative disease most commonly caused by autosomal dominant mutations in the SPG4 gene encoding the microtubule-severing protein spastin. We hypothesise that SPG4-HSP is attributable to reduced spastin function because of haploinsufficiency; thus, therapeutic approaches which elevate levels of the wild-type spastin allele may be an effective therapy. However, until now, how spastin levels are regulated is largely unknown. Here, we show that the kinase HIPK2 regulates spastin protein levels in proliferating cells, in differentiated neurons and in vivo. Our work reveals that HIPK2-mediated phosphorylation of spastin at S268 inhibits spastin K48-poly-ubiquitination at K554 and prevents its neddylation-dependent proteasomal degradation. In a spastin RNAi neuronal cell model, overexpression of HIPK2, or inhibition of neddylation, restores spastin levels and rescues neurite defects. Notably, we demonstrate that spastin levels can be restored pharmacologically by inhibiting its neddylation-mediated degradation in neurons derived from a spastin mouse model of HSP and in patient-derived cells, thus revealing novel therapeutic targets for the treatment of SPG4-HSP.


Assuntos
Proteínas de Transporte/metabolismo , Proteínas Serina-Treonina Quinases/metabolismo , Paraplegia Espástica Hereditária/metabolismo , Espastina/metabolismo , Animais , Proteínas de Transporte/fisiologia , Modelos Animais de Doenças , Regulação da Expressão Gênica/genética , Células HeLa , Humanos , Camundongos , Camundongos Knockout , Microtúbulos/metabolismo , Mutação , Neuritos/metabolismo , Doenças Neurodegenerativas/metabolismo , Doenças Neurodegenerativas/fisiopatologia , Neurônios/metabolismo , Proteínas Serina-Treonina Quinases/fisiologia , Proteólise , Paraplegia Espástica Hereditária/fisiopatologia , Espastina/fisiologia , Sinapses/metabolismo , Ubiquitinação
3.
Hum Mol Genet ; 28(7): 1136-1152, 2019 04 01.
Artigo em Inglês | MEDLINE | ID: mdl-30520996

RESUMO

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.


Assuntos
Paraplegia Espástica Hereditária/genética , Espastina/genética , Animais , Transporte Axonal/fisiologia , Axônios/metabolismo , Modelos Animais de Doenças , Mutação com Ganho de Função/genética , Haploinsuficiência , Haplótipos , Camundongos , Camundongos Transgênicos , Microtúbulos/metabolismo , Proteínas Mutantes/genética , Mutação , Neurônios/metabolismo , Paraplegia Espástica Hereditária/fisiopatologia , Espastina/fisiologia
4.
Postepy Biochem ; 62(1): 52-59, 2016.
Artigo em Polonês | MEDLINE | ID: mdl-28132445

RESUMO

ATP-dependent severing activity of microtubule severing proteins leads to the local destabilization of the microtubule structure and causes shortening or disassembly of the existing microtubules or formation of the numerous short microtubule fragments that serve as templates during new microtubule polymerization. Microtubule severing protein-dependent rearrangement of the microtubular cytoskeleton plays an important role in the numerous cellular processes including chromosome segregation during meiosis and mitosis, cells migration, dendrites and axon formation, cilia assembly and arrangement of the cortical microtubules in plant cells.


Assuntos
ATPases Associadas a Diversas Atividades Celulares/fisiologia , Katanina/fisiologia , Proteínas Associadas aos Microtúbulos/fisiologia , Microtúbulos/metabolismo , Espastina/fisiologia , ATPases Associadas a Diversas Atividades Celulares/metabolismo , Trifosfato de Adenosina/metabolismo , Animais , Axônios/metabolismo , Axônios/fisiologia , Movimento Celular , Cílios/metabolismo , Cílios/fisiologia , Humanos , Katanina/metabolismo , Meiose , Proteínas Associadas aos Microtúbulos/metabolismo , Mitose , Fenômenos Fisiológicos Vegetais , Plantas/metabolismo , Espastina/metabolismo
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