Autophagosomes initiate distally and mature during transport toward the cell soma in primary neurons

Maday, Sandra; Wallace, Kathleen; Holzbaur, Erika L.F.

doi:10.1083/jcb.201106120

Cited by 586 publications

(813 citation statements)

References 30 publications

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“…This model is supported by multiple studies that point to an active process of lysosome biogenesis within axons that begins with the merging of organelles derived from the endocytic and autophagic pathways followed by further maturation toward lysosomes that is coupled to their retrograde transport (44)(45)(46)(47)(48)(49). More specifically, there is a high level of constitutive autophagosome biogenesis that occurs within distal regions of axons (46,48,50,51). These autophagosomes fuse with endosomes and acquire endocytic cargos and late endosome/lysosome marker proteins such as LAMP1 (46,48,49).…”

Section: Discussionmentioning

confidence: 52%

“…More specifically, there is a high level of constitutive autophagosome biogenesis that occurs within distal regions of axons (46,48,50,51). These autophagosomes fuse with endosomes and acquire endocytic cargos and late endosome/lysosome marker proteins such as LAMP1 (46,48,49). These initial steps of convergence between the endocytic and autophagic pathways are accompanied by luminal acidification and coincide with a switch toward a predominantly dynein-driven transport in the retrograde direction (48,52).…”

Section: Discussionmentioning

confidence: 99%

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Massive accumulation of luminal protease-deficient axonal lysosomes at Alzheimer’s disease amyloid plaques

Gowrishankar

Yuan

et al. 2015

Proc. Natl. Acad. Sci. U.S.A.

327

326

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Through a comprehensive analysis of organellar markers in mouse models of Alzheimer’s disease, we document a massive accumulation of lysosome-like organelles at amyloid plaques and establish that the majority of these organelles reside within swollen axons that contact the amyloid deposits. This close spatial relationship between axonal lysosome accumulation and extracellular amyloid aggregates was observed from the earliest stages of β-amyloid deposition. Notably, we discovered that lysosomes that accumulate in such axons are lacking in multiple soluble luminal proteases and thus are predicted to be unable to efficiently degrade proteinaceous cargos. Of relevance to Alzheimer’s disease, β-secretase (BACE1), the protein that initiates amyloidogenic processing of the amyloid precursor protein and which is a substrate for these proteases, builds up at these sites. Furthermore, through a comparison between the axonal lysosome accumulations at amyloid plaques and neuronal lysosomes of the wild-type brain, we identified a similar, naturally occurring population of lysosome-like organelles in neuronal processes that is also defined by its low luminal protease content. In conjunction with emerging evidence that the lysosomal maturation of endosomes and autophagosomes is coupled to their retrograde transport, our results suggest that extracellular β-amyloid deposits cause a local impairment in the retrograde axonal transport of lysosome precursors, leading to their accumulation and a blockade in their further maturation. This study both advances understanding of Alzheimer’s disease brain pathology and provides new insights into the subcellular organization of neuronal lysosomes that may have broader relevance to other neurodegenerative diseases with a lysosomal component to their pathology.

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Section: Discussionmentioning

confidence: 52%

Section: Discussionmentioning

confidence: 99%

Massive accumulation of luminal protease-deficient axonal lysosomes at Alzheimer’s disease amyloid plaques

Gowrishankar

Yuan

et al. 2015

Proc. Natl. Acad. Sci. U.S.A.

327

326

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“…In the neurons, autophagosomes formed in distal axons mature and fuse with late endosomes and/or lysosomes during transport towards the cell soma. 66 It was shown that disruption of autophagosome transport on microtubules by vinblastin led to the inhibition of autophagosome and lysosome fusion and to accumulation of these vesicles. 3,67 Dynein inhibition by EHNA suppressed fusion of autophagosomes and lysosomes.…”

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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“…109 In addition, distal formation and retrograde transport of autophagosomes in axons of primary neurons have been reported and mitochondrial markers have been observed in these autophagosomes. 110 Nevertheless, it is not certain that retrograde transport of an autophagosome to the soma is strictly required as lysosomal markers have also been found to colocalize with autophagosomes in distal axons, implying that lysosomal degradation can be completed outside the soma. 109,110 It bears mentioning that the above studies have looked at the total population of autophagosomes, and the fate of mitophagosomes formed in response to damage in particular have not been analyzed.…”

Section: Mitophagy In Neuronsmentioning

confidence: 99%

“…110 Nevertheless, it is not certain that retrograde transport of an autophagosome to the soma is strictly required as lysosomal markers have also been found to colocalize with autophagosomes in distal axons, implying that lysosomal degradation can be completed outside the soma. 109,110 It bears mentioning that the above studies have looked at the total population of autophagosomes, and the fate of mitophagosomes formed in response to damage in particular have not been analyzed. Understanding the dynamics of damaged neuronal mitochondria and the molecular players of neuronal mitophagy will help elucidate the contribution of mitochondrial dysfunction to neurodegenerative diseases.…”

Section: Mitophagy In Neuronsmentioning

confidence: 99%

The pathways of mitophagy for quality control and clearance of mitochondria

2012

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Selective autophagy of mitochondria, known as mitophagy, is an important mitochondrial quality control mechanism that eliminates damaged mitochondria. Mitophagy also mediates removal of mitochondria from developing erythrocytes, and contributes to maternal inheritance of mitochondrial DNA through the elimination of sperm-derived mitochondria. Recent studies have identified specific regulators of mitophagy that ensure selective sequestration of mitochondria as cargo. In yeast, the mitochondrial outer membrane protein autophagy-related gene 32 (ATG32) recruits the autophagic machinery to mitochondria, while mammalian Nix is required for degradation of erythrocyte mitochondria. The elimination of damaged mitochondria in mammals is mediated by a pathway comprised of PTEN-induced putative protein kinase 1 (PINK1) and the E3 ubiquitin ligase Parkin. PINK1 and Parkin accumulate on damaged mitochondria, promote their segregation from the mitochondrial network, and target these organelles for autophagic degradation in a process that requires Parkin-dependent ubiquitination of mitochondrial proteins. Here we will review recent advances in our understanding of the different pathways of mitophagy. In addition, we will discuss the relevance of these pathways in neurons where defects in mitophagy have been implicated in neurodegeneration. Facts Mitophagy mediates clearance of damaged mitochondria, and is also involved in the removal of mitochondria from maturing erythrocytes and eliminating sperm-derived mitochondria after fertilization. In yeast, the mitochondrial outer membrane protein autophagy-related gene 32 (ATG32) recruits the core autophagic machinery to mitochondria for their selective removal. A pathway containing PTEN-induced putative protein kinase 1 (PINK1) and Parkin responds to loss of mitochondrial membrane potential by targeting damaged mitochondria for clearance. The PINK1/Parkin pathway is triggered when PINK1 is stabilized on the outer membrane of damaged mitochondria, where it facilitates recruitment of cytosolic Parkin. Damaged mitochondria are prevented from moving and fusing with the mitochondrial reticulum in preparation for their mitophagic clearance. Open QuestionsHow distinct are the mitophagy pathways triggered by different stimuli or conditions?To what extent does Parkin activate mitophagy by causing the degradation of mitochondrial surface proteins or hyperubiquitinating the mitochondrial surface? How do PINK1 and Parkin interact with one another and with substrates on the mitochondrial surface in causing mitophagy? In contrast to the remarkable conservation of the core autophagic machinery, why are mitophagy-specific genes so little conserved between yeast and mammals? How best should mitophagy be triggered by researchers probing physiologically relevant pathways?The mitochondrion is an important actor in the life of a eukaryotic cell, but, like all good actors, a mitochondrion needs to exit the stage at the right time. Mitophagy removes mitochondria once they have played their part. This artic...

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Autophagosomes initiate distally and mature during transport toward the cell soma in primary neurons

Abstract: Autophagosome biogenesis and maturation in primary neurons is a constitutive process that is spatially and temporally regulated along the axon.

Cited by 586 publications

References 30 publications

Massive accumulation of luminal protease-deficient axonal lysosomes at Alzheimer’s disease amyloid plaques

Massive accumulation of luminal protease-deficient axonal lysosomes at Alzheimer’s disease amyloid plaques

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

The pathways of mitophagy for quality control and clearance of mitochondria

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