Parkin contributes to synaptic vesicle autophagy in Bassoon-deficient mice

Hoffmann-Conaway, Sheila; Brockmann, Marisa M; Schneider, Katharina; Annamneedi, Anil; Rahman, Kazi Atikur; Bruns, Christine; Textoris-Taube, Kathrin; Trimbuch, Thorsten; Rosenmund, Christian; Gundelfinger, Eckart D.; Garner, Craig C.; Montenegro-Venegas, Carolina

doi:10.7554/elife.56590

Cited by 50 publications

(46 citation statements)

References 79 publications

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“…These studies provide evidence for the involvement of autophagy in the turnover of SVs, and presence of SVs in autophagosomes has been indeed reported at EM level (see for example [71]). However, degradation of SVs and SV proteins via the endolysosomal system was also reported (see "Molecular organizers and cargo of the endolysosomal system at presynaptic sites") and the vast majority of synaptic autophagosomes are devoid of SVs.…”

Section: Substrates Of Autophagy At Boutonssupporting

confidence: 74%

“…Surprisingly, how degradation of SVs and SV proteins takes place and what is the underlying predominant mechanism is currently unclear (see also “ Molecular organizers and cargo of the endolysosomal system at presynaptic sites ”). A few studies have identified SVs as substrates of the autophagy pathway [ 25 , 50 , 71 , 72 ] and recent evidence describes the involvement of Rab26-dependent pathways in mediating the delivery of SVs to pre-autophagosomal membranes [ 50 , 72 ]. Accordingly, Rab26 associates to SVs and is particularly enriched in large membrane-surrounded clusters that are also positive for proteins of the early autophagy machinery such as ATG16L1, Rab33B and LC3b-II and whose formation correlates with high levels of Rab26 [ 50 ], suggesting that this protein acts as an intermediate between SVs and the autophagy machinery (Fig.…”

Section: The Function Of Autophagy At Axonal Boutonsmentioning

confidence: 99%

“…In a recent study it was reported that Bassoon mediates the ubiquitination of SV proteins via two E3-ubiquitin ligases, Siah1 and Parkin, which in turn drives SV proteins for autophagy degradation (Fig. 2 i) [ 71 ]. Accordingly, absence of Bassoon causes an increase of ubiquitinated SV proteins that leads to a decrease of SV protein levels in an autophagy-dependent manner, and this correlates with a smaller SV pool size and an overall higher rate of SV protein turnover found in Bassoon KO neurons [ 71 ].…”

Section: The Function Of Autophagy At Axonal Boutonsmentioning

confidence: 99%

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Autophagy and the endolysosomal system in presynaptic function

Andres-Alonso

Kreutz

Karpova

2020

Cell. Mol. Life Sci.

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The complex morphology of neurons, the specific requirements of synaptic neurotransmission and the accompanying metabolic demands create a unique challenge for proteostasis. The main machineries for neuronal protein synthesis and degradation are localized in the soma, while synaptic junctions are found at vast distances from the cell body. Sophisticated mechanisms must, therefore, ensure efficient delivery of newly synthesized proteins and removal of faulty proteins. These requirements are exacerbated at presynaptic sites, where the demands for protein turnover are especially high due to synaptic vesicle release and recycling that induces protein damage in an intricate molecular machinery, and where replacement of material is hampered by the extreme length of the axon. In this review, we will discuss the contribution of the two major pathways in place, autophagy and the endolysosomal system, to presynaptic protein turnover and presynaptic function. Although clearly different in their biogenesis, both pathways are characterized by cargo collection and transport into distinct membrane-bound organelles that eventually fuse with lysosomes for cargo degradation. We summarize the available evidence with regard to their degradative function, their regulation by presynaptic machinery and the cargo for each pathway. Finally, we will discuss the interplay of both pathways in neurons and very recent findings that suggest non-canonical functions of degradative organelles in synaptic signalling and plasticity.

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Section: Substrates Of Autophagy At Boutonssupporting

confidence: 74%

Section: The Function Of Autophagy At Axonal Boutonsmentioning

confidence: 99%

Section: The Function Of Autophagy At Axonal Boutonsmentioning

confidence: 99%

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Autophagy and the endolysosomal system in presynaptic function

Andres-Alonso

Kreutz

Karpova

2020

Cell. Mol. Life Sci.

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“…Sections were incubated in 10 mM sodium citrate at 80 °C for 20 min and then washed three times in PBS. Tissue was blocked for 1 h with 5% normal donkey serum or 5% normal goat serum (Abcam) at room temperature and incubated at 4 °C with primary antibodies against c-Fos (1:2000, Synaptic Systems, Cat# 226003; RRID: AB_2231974 ) [ 25 ], dsRed (1:1000, Clontech, Cat# 632392; RRID: AB_2801258 ) [ 26 ], GFP (1:1000, Abcam, Cat# ab13970; RRID: AB_300798 ) [ 27 ], TH (1:200, Cat# 22941; RRID: AB_572268 , Immunostar) [ 28 ], PrRP (1:1000, Abcam, Cat# ab251707), Ha (1:1000, Cell Signaling Technology, Ca# 3724; RRID: AB_1549585 ) [ 29 ] GFRAL (1:200, Thermo Fisher Scientific, Cat# PA5-47769; RRID: AB_2607220 ), and SYP (1:500, Synaptic Systems, Cat# 101 011; RRID: AB_887824 ) [ 30 ]. The sections were then mounted on slides and coverslipped with Prolong Diamond (Thermo Fisher Scientific).…”

Section: Methodsmentioning

confidence: 99%

Nutrient sensing in the nucleus of the solitary tract mediates non-aversive suppression of feeding via inhibition of AgRP neurons

Tsang

Nuzzaci

Darwish

et al. 2020

Molecular Metabolism

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The nucleus of the solitary tract (NTS) is emerging as a major site of action for the appetite-suppressive effects of leading pharmacotherapies currently investigated to treat obesity. However, our understanding of how NTS neurons regulate appetite remains incomplete. Objectives In this study, we used NTS nutrient sensing as an entry point to characterize stimulus-defined neuronal ensembles engaged by the NTS to produce physiological satiety. Methods We combined histological analysis, neuroanatomical assessment using inducible viral tracing tools, and functional tests to characterize hindbrain-forebrain circuits engaged by NTS leucine sensing to suppress hunger. Results We found that NTS detection of leucine engages NTS prolactin-releasing peptide (PrRP) neurons to inhibit AgRP neurons via a population of leptin receptor-expressing neurons in the dorsomedial hypothalamus. This circuit is necessary for the anorectic response to NTS leucine, the appetite-suppressive effect of high-protein diets, and the long-term control of energy balance. Conclusions These results extend the integrative capability of AgRP neurons to include brainstem nutrient sensing inputs.

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“…Deletion of both Bsn and Pclo increases ubiquitination of SV proteins and leads to progressive neuronal degeneration, which is likely driven by destabilization of SV cluster at presynaptic sites and their degradation by proteasomal and endo-lysosomal pathways [ 46 ]. Recently, Bsn has been reported to interact with autophagy-associated E3-like ligase Atg5 and suppress its activity, controlling thereby presynaptic autophagy [ 20 , 36 ]. Thus, Bsn regulates ubiquitination and degradation of synaptic proteins via proteasomal, endo- lysosomal and autophagocytic pathways, which supports recently emerging view of the large functional interplay among these pathways in neurons [ 47 ].…”

Section: Introductionmentioning

confidence: 99%

Bassoon inhibits proteasome activity via interaction with PSMB4

Montenegro-Venegas

Fieńko

Anni

et al. 2020

Cell. Mol. Life Sci.

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Proteasomes are protein complexes that mediate controlled degradation of damaged or unneeded cellular proteins. In neurons, proteasome regulates synaptic function and its dysfunction has been linked to neurodegeneration and neuronal cell death. However, endogenous mechanisms controlling proteasomal activity are insufficiently understood. Here, we describe a novel interaction between presynaptic scaffolding protein bassoon and PSMB4, a β subunit of the 20S core proteasome. Expression of bassoon fragments that interact with PSMB4 in cell lines or in primary neurons attenuates all endopeptidase activities of cellular proteasome and induces accumulation of several classes of ubiquitinated and non-ubiquitinated substrates of the proteasome. Importantly, these effects are distinct from the previously reported impact of bassoon on ubiquitination and autophagy and might rely on a steric interference with the assembly of the 20S proteasome core. In line with a negative regulatory role of bassoon on endogenous proteasome we found increased proteasomal activity in the synaptic fractions prepared from brains of bassoon knock-out mice. Finally, increased activity of proteasome and lower expression levels of synaptic substrates of proteasome could be largely normalized upon expression of PSMB4-interacting fragments of bassoon in neurons derived from bassoon deficient mice. Collectively, we propose that bassoon interacts directly with proteasome to control its activity at presynapse and thereby it contributes to a compartment-specific regulation of neuronal protein homeostasis. These findings provide a mechanistic explanation for the recently described link of bassoon to human diseases associated with pathological protein aggregation. Graphic Abstract Presynaptic cytomatrix protein bassoon (Bsn) interacts with PSMB4, the β7 subunit of 20S core proteasome, via three independent interaction interfaces. Bsn inhibits proteasomal proteolytic activity and degradation of different classes of proteasomal substrates presumably due to steric interference with the assembly of 20S core of proteasome. Upon Bsn deletion in neurons, presynaptic substrates of the proteasome are depleted, which can be reversed upon expression of PSMB4-interacting interfaces of Bsn. Taken together, bsn controls the degree of proteasome degradation within the presynaptic compartment and thus, contributes to the regulation of synaptic proteome

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Parkin contributes to synaptic vesicle autophagy in Bassoon-deficient mice

Cited by 50 publications

References 79 publications

Autophagy and the endolysosomal system in presynaptic function

Autophagy and the endolysosomal system in presynaptic function

Nutrient sensing in the nucleus of the solitary tract mediates non-aversive suppression of feeding via inhibition of AgRP neurons

Bassoon inhibits proteasome activity via interaction with PSMB4

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