Impaired JIP3-dependent axonal lysosome transport promotes amyloid plaque pathology

Gowrishankar, Swetha; Wu, Yumei; Ferguson, Shawn M.

doi:10.1083/jcb.201612148

Cited by 106 publications

(161 citation statements)

References 61 publications

(118 reference statements)

Supporting

Mentioning

151

Contrasting

Order By: Relevance

“…MDVs that are shed by mitochondria may be transported to lysosomes independent of the mitochondrion from which they arose. Furthermore, although lysosomes are most abundant in the soma, there is evidence for lysosomes in axons as well (Ashrafi et al, 2014; Maday and Holzbaur, 2014) and for late endosomes arising in distal axons that mature into lysosomes and increase in their proteolytic capacity en route as they move retrograde (Gowrishankar et al, 2017). The axonal pool of lysosomes may be sufficient to mediate clearance, when needed, in an otherwise healthy neuron.…”

Section: Where Are Mitochondria Cleared?mentioning

confidence: 99%

Mitostasis in Neurons: Maintaining Mitochondria in an Extended Cellular Architecture

Misgeld

Schwarz

2017

Neuron

426

409

View full text Add to dashboard Cite

SUMMARY Neurons have more extended and complex shapes than other cells and consequently face a greater challenge in distributing and maintaining mitochondria throughout their arbors. Neurons can last a lifetime, but proteins turn over rapidly. Mitochondria, therefore, need constant rejuvenation no matter how far they are from the soma. Axonal transport of mitochondria and mitochondrial fission and fusion contribute to this rejuvenation, with local protein synthesis likely also to be involved. Maintenance of a healthy mitochondrial population also requires the clearance of damaged proteins and organelles. This involves degradation of individual proteins, sequestration in mitochondria-derived vesicles, organelle degradation by mitophagy and macroautophagy, and in some cases transfer to glial cells. Both long-range transport and local processing are thus at work in achieving neuronal mitostasis – the maintenance of an appropriately distributed pool of healthy mitochondria for the duration of a neuron’s life. Accordingly, defects in the processes that support mitostasis are significant contributors to neurodegenerative disorders.

show abstract

Section: Where Are Mitochondria Cleared?mentioning

confidence: 99%

Mitostasis in Neurons: Maintaining Mitochondria in an Extended Cellular Architecture

Misgeld

Schwarz

2017

Neuron

426

409

View full text Add to dashboard Cite

show abstract

“…Interestingly, other organelles such as lysosomes show a high dynamics in mature axons, with a tendency for retrograde movement that correlates with their maturation (37). Upon lesion we observed a significant decrease of their velocity.…”

Section: Discussionmentioning

confidence: 60%

“…Anterograde and retrograde movements were equally not affected by axon injury (Figure 5G). In contrast, we observed that lysosomes, tracked with LysoTracker, were extremely motile ( Figure 5K-Q, Video 7A, B), with a bidirectional movement predominantly retrograde, as described for maturing lysosomes tracked with LysoTracker in axons (37). Indeed, 90% of lysosomes were moving (both anterogradely and retrogradely) in intact axons ( Figure 5P) with an average retrograde speed of 0.6µm/s and an average anterograde speed of 0.3µm/s (Figure 5N).…”

Section: /27mentioning

confidence: 51%

Adult mouse retina explants: an ex vivo window to explore central nervous system diseases

Schaeffer

Tardy

Albert

et al. 2020

Preprint

View full text Add to dashboard Cite

When the developing central nervous system (CNS) becomes mature, it loses its ability to regenerate. Therefore, any insult to adult CNS leads to a permanent and irreversible loss of motor and cognitive functions. For a long time, much effort has been deployed to uncover mechanisms of axon regeneration in the CNS. It is now well understood that neurons themselves lose axon regeneration capabilities during development, and also after a lesion or in pathological conditions.Since then, many molecular pathways such as mTOR and JAK/STAT have been associated with axon regeneration. However, no functional recovery has been achieved yet. Today, there is a need not only to identify new molecules implicated in adult CNS axon regeneration, but also to decipher the fine molecular mechanisms associated with regeneration failure. This is critical to make progress in our understanding of neuroprotection and neuroregeneration and for the development of new therapeutic strategies. In this context, it remains particularly challenging to address molecular mechanisms in in vivo models of CNS regeneration. The extensive use of embryonic neurons as in vitro model is a source of bias, as they have the intrinsic competence to grow their axon upon injury, unlike mature neurons. In addition, this type of dissociated neuronal cultures lack a tissue environment to recapitulate properly molecular and cellular events in vitro. Here, we propose to use cultures of adult retina explants to fill this gap. The visual system -which includes the retina and optic nerve -is a gold-standard model to study axon regeneration and degeneration in the mature CNS. Cultures of adult retina explants combine two advantages: they have the simplicity of embryonic neurons cultures and they recapitulate all the aspects of in vivo features in the tissue. Importantly, it is the most appropriate tool to date to isolate molecular and cellular events of axon regeneration and degeneration of the adult CNS in a dish. This ex vivo system allows to set up a large range of experiments to decipher the fine molecular and cellular regulations underlying mature CNS axon growth.

show abstract

“…On the other side, the GWAS-identified genes, CELF1, NME8, and CASS4, are involved in axonal transport (Giri, Zhang, & Lü, 2016). It is important to highlight that impairment of lysosomal axonal transport in AD has been linked to the aggregation of Aβ in the brain of mice (Gowrishankar, Wu, & Ferguson, 2017;Gowrishankar et al, 2015). Finally, genes belonging to endocytosis/trafficking pathways have also been identified as risk factors for AD in several GWAS studies (Karch & Goate, 2015, see Section 4.2 and Table 1).…”

Section: Genetic and Biological Evidence For A Role Of Degradative mentioning

confidence: 99%

“…Neuronal lysosomal dysfunction increases the accumulation of APP-CTFs in endosomal compartments (Boland et al, 2010;Gowrishankar et al, 2017;Guix et al, 2017;Miranda et al, 2018) and its secretion via exosomes (Miranda et al, 2018). Autophagy has been also involved in APP-CTF degradation via the GWAS-identified risk factor PICALM (Tian et al, 2013) although a different study did not find a connection between macroautophagy and APP metabolism (Boland et al, 2010).…”

Section: Enhanced Secretion Of Exosomes May Trigger Increased Aβ Gementioning

confidence: 99%

The interplay between aging‐associated loss of protein homeostasis and extracellular vesicles in neurodegeneration

Guix

2019

J of Neuroscience Research

View full text Add to dashboard Cite

The finding of an effective cure or treatment for neurodegenerative diseases is one of the biggest challenges for this century. Although these diseases show different clinical manifestations, the presence of toxic protein aggregates in the brain of patients is a common feature to all of them, suggesting a loss of protein homeostasis.Aging, the primary risk factor for the majority of neurodegenerative disorders, is linked to the impairment of degradative compartments such as lysosomes and autophagosomes. Besides, many genetic factors for Alzheimer's disease, Parkinson's disease, or frontotemporal dementia, as examples of frequent neurodegenerative diseases, are causative of endo-lysosomal and autophagosomal dysfunctions. There is scientific evidence suggesting that neurons can counteract the accumulation of undegraded cellular material by the secretion of extracellular vesicles (EVs), which are vesicles with a size ranging from 50 to 100 nm generated in a type of endosomal compartment named multivesicular body. EVs play a crucial role in removing cellular waste, promoting protein aggregation, and spreading toxic protein aggregates in the brain of patients. In this review, the interplay between the impairment of degradative compartments, the secretion of EVs, and their pathological/beneficial role in neurodegeneration is described.

show abstract

Impaired JIP3-dependent axonal lysosome transport promotes amyloid plaque pathology

Cited by 106 publications

References 61 publications

Mitostasis in Neurons: Maintaining Mitochondria in an Extended Cellular Architecture

Mitostasis in Neurons: Maintaining Mitochondria in an Extended Cellular Architecture

Adult mouse retina explants: an ex vivo window to explore central nervous system diseases

The interplay between aging‐associated loss of protein homeostasis and extracellular vesicles in neurodegeneration

Contact Info

Product

Resources

About