Ubiquitin Homeostasis Is Critical for Synaptic Development and Function

Chen, Ping Chung; Bhattacharyya, Budhaditya; Hanna, John; Minkel, Heather; Wilson, Julie A.; Finley, Daniel; Miller, Richard J.; Wilson, Scott

doi:10.1523/jneurosci.2922-11.2011

Cited by 90 publications

(116 citation statements)

References 33 publications

(48 reference statements)

Supporting

Mentioning

108

Contrasting

Order By: Relevance

“…Notably, all the negative effects observed in the ax J phenotype were attributed to the decreased free ubiquitin levels, resulting ultimately in synaptic dysfunction. Restoring free ubiquitin levels prevented the early death at 8 weeks of age, body weight loss and presynaptic dysfunction observed in the ataxic mice (Chen et al, 2011). The deficit in neurotransmitter release in the ax J mice is in accordance with the results showing that inhibition of Uch-L1, another DUB abundantly expressed in neurons, also decreases free ubiquitin levels, thus increasing the number of synaptic vesicles (Cartier et al, 2009).…”

Section: Role Of Ups In Nervous Systemsupporting

confidence: 83%

Role of the ubiquitin–proteasome system in brain ischemia: Friend or foe?

Caldeira

Salazar

Curcio

et al. 2014

Progress in Neurobiology

110

View full text Add to dashboard Cite

A B S T R A C TThe ubiquitin-proteasome system (UPS) is a catalytic machinery that targets numerous cellular proteins for degradation, thus being essential to control a wide range of basic cellular processes and cell survival. Degradation of intracellular proteins via the UPS is a tightly regulated process initiated by tagging a target protein with a specific ubiquitin chain. Neurons are particularly vulnerable to any change in protein composition, and therefore the UPS is a key regulator of neuronal physiology. Alterations in UPS activity may induce pathological responses, ultimately leading to neuronal cell death. Brain ischemia triggers a complex series of biochemical and molecular mechanisms, such as an inflammatory response, an exacerbated production of misfolded and oxidized proteins, due to oxidative stress, and the breakdown of cellular integrity mainly mediated by excitotoxic glutamatergic signaling. Brain ischemia also damages protein degradation pathways which, together with the overproduction of damaged proteins and consequent upregulation of ubiquitin-conjugated proteins, contribute to the accumulation of ubiquitincontaining proteinaceous deposits. Despite recent advances, the factors leading to deposition of such aggregates after cerebral ischemic injury remain poorly understood. This review discusses the current knowledge on the role of the UPS in brain function and the molecular mechanisms contributing to UPS dysfunction in brain ischemia with consequent accumulation of ubiquitin-containing proteins. Chemical inhibitors of the proteasome and small molecule inhibitors of deubiquitinating enzymes, which promote the degradation of proteins by the proteasome, were both shown to provide neuroprotection in brain ischemia, and this apparent contradiction is also discussed in this review. ß

show abstract

Section: Role Of Ups In Nervous Systemsupporting

confidence: 83%

Role of the ubiquitin–proteasome system in brain ischemia: Friend or foe?

Caldeira

Salazar

Curcio

et al. 2014

Progress in Neurobiology

110

View full text Add to dashboard Cite

show abstract

“…Increased transcription of endogenous USP14, a DUB demonstrated to maintain monoubiquitin in mice (37)(38)(39)(40), may account for monoubiquitin not being depleted when DmUSP5 is knocked down in developing flies. When we tested whether exogenous USP14 alleviates lethality caused by knockdown of DmUSP5, we found that this was not the case ( Fig.…”

Section: Dmusp5 Knockdown Leads To Increased Conjugated Ubiquitin Spementioning

confidence: 99%

USP5 Is Dispensable for Monoubiquitin Maintenance in Drosophila

Ristic

Tsou

Guzi

et al. 2016

Journal of Biological Chemistry

View full text Add to dashboard Cite

Ubiquitination is a post-translational modification that regulates most cellular pathways and processes, including degradation of proteins by the proteasome. Substrate ubiquitination is controlled at various stages, including through its reversal by deubiquitinases (DUBs). A critical outcome of this process is the recycling of monoubiquitin. One DUB whose function has been proposed to include monoubiquitin recycling is USP5. Here, we investigated whether Drosophila USP5 is important for maintaining monoubiquitin in vivo. We found that the fruit fly orthologue of USP5 has catalytic preferences similar to its human counterpart and that this DUB is necessary during fly development. Our biochemical and genetic experiments indicate that reduction of USP5 does not lead to monoubiquitin depletion in developing flies. Also, introduction of exogenous ubiquitin does not suppress developmental lethality caused by loss of endogenous USP5. Our work indicates that a primary physiological role of USP5 is not to recycle monoubiquitin for reutilization, but that it may involve disassembly of conjugated ubiquitin to maintain proteasome function.

show abstract

“…Autophagy and the ubiquitin-proteasome system are major pathways for protein degradation in cells. Accumulating evidence has indicated the importance of protein degradation via the ubiquitin-proteasome system, which is mainly responsible for the turnover of short-lived cytosolic proteins, in regulating synaptic growth [13][14][15][16] . Highwire (Hiw), an E3 ubiquitin ligase that mediates key steps in the protein ubiquitination process, negatively governs synaptic growth at the Drosophila NMJ [17,18] .…”

Section: Autophagy In Synaptogenesismentioning

confidence: 99%

Autophagy in synaptic development, function, and pathology

et al. 2015

View full text Add to dashboard Cite

In the nervous system, neurons contact each other to form neuronal circuits and drive behavior, relying heavily on synaptic connections. The proper development and growth of synapses allows functional transmission of electrical information between neurons or between neurons and muscle fi bers. Defects in synapse-formation or development lead to many diseases. Autophagy, a major determinant of protein turnover, is an essential process that takes place in developing synapses. During the induction of autophagy, proteins and cytoplasmic components are encapsulated in autophagosomes, which fuse with lysosomes to form autolysosomes. The cargoes are subsequently degraded and recycled. However, aberrant autophagic activity may lead to synaptic dysfunction, which is a common pathological characteristic in several disorders. Here, we review the current understanding of autophagy in regulating synaptic development and function. In addition, autophagy-related synaptic dysfunction in human diseases is also summarized.

show abstract

Ubiquitin Homeostasis Is Critical for Synaptic Development and Function

Cited by 90 publications

References 33 publications

Role of the ubiquitin–proteasome system in brain ischemia: Friend or foe?

Role of the ubiquitin–proteasome system in brain ischemia: Friend or foe?

USP5 Is Dispensable for Monoubiquitin Maintenance in Drosophila

Autophagy in synaptic development, function, and pathology

Contact Info

Product

Resources

About