Dynein mutations impair autophagic clearance of aggregate-prone proteins

Ravikumar, Brinda; Acevedo-Arozena, Abraham; Imarisio, Sara; Berger, Zdenek; Vacher, Coralie; O’Kane, Cahir J.; Brown, Steve; Rubinsztein, David C.

doi:10.1038/ng1591

Cited by 416 publications

(342 citation statements)

References 30 publications

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“…3,67 Dynein inhibition by EHNA suppressed fusion of autophagosomes and lysosomes. 68 Dynactin 1, a member of the Dynactin complex, which is essential for dynein function in motility was also linked to autophagosomal transport. 69 RINT1 and Dynactin1 interact with ZW10 in a competitive manner 70 and it was suggested that the RINT1/ZW10 complex may play as an ER anchor for the Dynein-Dynactin complex carried vesicles.…”

Section: Discussionmentioning

confidence: 99%

Rint1 inactivation triggers genomic instability, ER stress and autophagy inhibition in the brain

et al. 2015

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Endoplasmic reticulum (ER) stress, defective autophagy and genomic instability in the central nervous system are often associated with severe developmental defects and neurodegeneration. Here, we reveal the role played by Rint1 in these different biological pathways to ensure normal development of the central nervous system and to prevent neurodegeneration. We found that inactivation of Rint1 in neuroprogenitors led to death at birth. Depletion of Rint1 caused genomic instability due to chromosome fusion in dividing cells. Furthermore, Rint1 deletion in developing brain promotes the disruption of ER and Cis/Trans Golgi homeostasis in neurons, followed by ER-stress increase. Interestingly, Rint1 deficiency was also associated with the inhibition of the autophagosome clearance. Altogether, our findings highlight the crucial roles of Rint1 in vivo in genomic stability maintenance, as well as in prevention of ER stress and autophagy.

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Section: Discussionmentioning

confidence: 99%

Rint1 inactivation triggers genomic instability, ER stress and autophagy inhibition in the brain

et al. 2015

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“…Autophagosomes move bidirectionally along microtubules. Their centripetal movement is dependent on the dynein motor [80,81]. Two types of fusion have been documented [77]: 1, complete fusion of the autophagosome with the lysosome; 2, transfer of material from the autophagosome to the lysosomal compartment following a kiss-and-run fusion process in which two separate vesicles are maintained [49].…”

Section: Microtubules Destabilization Of Microtubules By Eithermentioning

confidence: 99%

Overview of macroautophagy regulation in mammalian cells

et al. 2010

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Macroautophagy is a multistep, vacuolar, degradation pathway terminating in the lysosomal compartment, and it is of fundamental importance in tissue homeostasis. In this review, we consider macroautophagy in the light of recent advances in our understanding of the formation of autophagosomes, which are double-membrane-bound vacuoles that sequester cytoplasmic cargos and deliver them to lysosomes. In most cases, this final step is preceded by a maturation step during which autophagosomes interact with the endocytic pathway. The discovery of AuTophaGyrelated genes has greatly increased our knowledge about the mechanism responsible for autophagosome formation, and there has also been progress in the understanding of molecular aspects of autophagosome maturation. Finally, the regulation of autophagy is now better understood because of the discovery that the activity of Atg complexes is targeted by protein kinases, and owing to the importance of nuclear regulation via transcription factors in regulating the expression of autophagy genes.

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“…It is now conceivable that changes in the enzymes of this complex could partially underlie autophagic dysfunction in neurodegenerative diseases [13] . In addition to defects in the induction process, genetic or functional alterations may occur in the autophagosome maturation, autolysosome formation, or autophagosome clearance processes [14] . For example, when components of the dynein motor machinery, such as dynein, dynactin or tubulin deacetylases, undergo changes, autophagosome-lysosome fusion is impaired, leading to decreased autophagic clearance of protein aggregates and enhanced neurotoxicity in animal models of HD and ALS [15][16][17] .…”

Section: Autophagic Flux Defects In Neurodegenerative Diseasesmentioning

confidence: 99%

Why should autophagic flux be assessed?

et al. 2013

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As autophagy is involved in cell growth, survival, development and death, impaired autophagic flux has been linked to a variety of human pathophysiological processes, including neurodegeneration, cancer, myopathy, cardiovascular and immune-mediated disorders. There is a growing need to identify and quantify the status of autophagic flux in different pathological conditions. Given that autophagy is a highly dynamic and complex process that is regulated at multiple steps, it is often assessed accurately. This perspective review article will focus on the autophagic flux defects in different human disorders and update the current methods of monitoring autophagic flux. This knowledge is essential for developing autophagy-related therapeutics for treating the diseases.

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Dynein mutations impair autophagic clearance of aggregate-prone proteins

Cited by 416 publications

References 30 publications

Rint1 inactivation triggers genomic instability, ER stress and autophagy inhibition in the brain

Rint1 inactivation triggers genomic instability, ER stress and autophagy inhibition in the brain

Overview of macroautophagy regulation in mammalian cells

Why should autophagic flux be assessed?

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