Axonal autophagosomes recruit dynein for retrograde transport through fusion with late endosomes

Cheng, Xiu; Zhou, Bing; Lin, Mei Yao; Cai, Qian; Sheng, Zu Hang

doi:10.1083/jcb.201412046

Cited by 205 publications

(263 citation statements)

References 38 publications

Supporting

Mentioning

235

Contrasting

Unclassified

Order By: Relevance

“…From these experiments we concluded that BORC-dependent anterograde transport of lysosomes is important for mobilization and disposal of autophagosomes from the distal axon. This conclusion is consistent with the notion that fusion of lysosomes with autophagosomes contributes to the dynein-dependent retrograde transport of the resulting autolysosomes, in addition to the degradation of their contents (31,53).…”

Section: Reduced Growth Cone Dynamics and Aberrant Autophagosomes Insupporting

confidence: 80%

“…The decreased size and dynamics of the growth cones in myrlysin-KD cells indicates a requirement of lysosomes for growth cone structure and function. We also observed that control neurons exhibited small vesicles labeled with the autophagy marker LC3, some that were stationary and others that moved mainly in the retrograde direction, as previously reported (30,31,52,53) (Fig. 7 E-H).…”

Section: Reduced Growth Cone Dynamics and Aberrant Autophagosomes Insupporting

confidence: 69%

“…neuron-specific processes (28)(29)(30)(31)(32)(33). Moreover, lysosome dysfunction underlies many neurodevelopmental and neurodegenerative disorders.…”

Section: Significancementioning

confidence: 99%

See 2 more Smart Citations

BORC/kinesin-1 ensemble drives polarized transport of lysosomes into the axon

Farı́as

Guardia

Pace

et al. 2017

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

185

234

View full text Add to dashboard Cite

The ability of lysosomes to move within the cytoplasm is important for many cellular functions. This ability is particularly critical in neurons, which comprise vast, highly differentiated domains such as the axon and dendrites. The mechanisms that control lysosome movement in these domains, however, remain poorly understood. Here we show that an ensemble of BORC, Arl8, SKIP, and kinesin-1, previously shown to mediate centrifugal transport of lysosomes in nonneuronal cells, specifically drives lysosome transport into the axon, and not the dendrites, in cultured rat hippocampal neurons. This transport is essential for maintenance of axonal growth-cone dynamics and autophagosome turnover. Our findings illustrate how a general mechanism for lysosome dispersal in nonneuronal cells is adapted to drive polarized transport in neurons, and emphasize the importance of this mechanism for critical axonal processes.

show abstract

Section: Reduced Growth Cone Dynamics and Aberrant Autophagosomes Insupporting

confidence: 80%

Section: Reduced Growth Cone Dynamics and Aberrant Autophagosomes Insupporting

confidence: 69%

See 1 more Smart Citation

BORC/kinesin-1 ensemble drives polarized transport of lysosomes into the axon

Farı́as

Guardia

Pace

et al. 2017

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

185

234

View full text Add to dashboard Cite

show abstract

“…9C). 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).…”

Section: Discussionsupporting

confidence: 48%

“…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%

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

View full text Add to dashboard Cite

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.

show abstract

Polyphenol Mediated Assembly: Tailored Nano‐Dredger Unblocks Axonal Autophagosomes Retrograde Transport Traffic Jam for Accelerated Alzheimer's Waste Clearance

Meng,

Li,

Yang

et al. 2024

Advanced Materials

View full text Add to dashboard Cite

Clear‐cut evidence has linked defective autophagy to Alzheimer's disease (AD). Recent studies underscore a unique hurdle in AD neuronal autophagy: impaired retrograde axonal transport of autophagosomes, potent enough to induce autophagic stress and neurodegeneration. Nonetheless, pertinent therapy is unavailable. Here, a novel combinational therapy composed of siROCK2 and lithospermic acid B (LA) is introduced, tailored to dredge blocked axonal autophagy by multi‐mitigating microtubule disruption, ATP depletion, oxidative stress, and autophagy initiation impediments in AD. Leveraging the recent discovery of multi‐interactions between polyphenol LA and siRNA, ε‐Poly‐L‐lysine, and anionic lipid nanovacuoles, LA and siROCK2 are successfully co‐loaded into a fresh nano‐drug delivery system, LIP@PL‐LA/siRC, via a ratio‐flexible and straightforward fabrication process. Further modification with the TPL peptide onto LIP@PL‐LA/siRC creates a brain‐neuron targeted, biocompatible, and pluripotent nanomedicine, named “Nano‐dredger” (T‐LIP@PL‐LA/siRC). Nano‐dredger efficiently accelerates axonal retrograde transport and lysosomal degradation of autophagosomes, thereby facilitating the clearance of neurotoxic proteins, improving neuronal complexity, and alleviating memory defects in 3×Tg‐AD transgenic mice. This study provides a fresh and flexible polyphenol/siRNA co‐delivery paradigm and furnishes conceptual proof that dredging axonal autophagy represents a promising AD therapeutic avenue.

show abstract

Axonal autophagosomes recruit dynein for retrograde transport through fusion with late endosomes

Abstract: Late endosome-loaded dynein–snapin complexes drive amphisome retrograde transport upon fusion of autophagosomes with late endosomes in distal axons.

Cited by 205 publications

References 38 publications

BORC/kinesin-1 ensemble drives polarized transport of lysosomes into the axon

BORC/kinesin-1 ensemble drives polarized transport of lysosomes into the axon

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

Polyphenol Mediated Assembly: Tailored Nano‐Dredger Unblocks Axonal Autophagosomes Retrograde Transport Traffic Jam for Accelerated Alzheimer's Waste Clearance

Contact Info

Product

Resources

About