Autophagy and the endolysosomal system in presynaptic function

AbstractThe 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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The Ubiquitin Proteasome System Acutely Regulates Presynaptic Protein Turnover and Synaptic Efficacy

Current Biology ◽

10.1016/s0960-9822(03)00338-5 ◽

2003 ◽

Vol 13 (11) ◽

pp. 899-910 ◽

Cited By ~ 151

Author(s):

Sean D Speese ◽

Nick Trotta ◽

Chris K Rodesch ◽

Bharathi Aravamudan ◽

Kendal Broadie

Keyword(s):

Protein Turnover ◽

Ubiquitin Proteasome System ◽

Synaptic Efficacy ◽

Ubiquitin Proteasome ◽

Presynaptic Protein

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The long noncoding RNA neuroLNC regulates presynaptic activity by interacting with the neurodegeneration-associated protein TDP-43

Science Advances ◽

10.1126/sciadv.aay2670 ◽

2019 ◽

Vol 5 (12) ◽

pp. eaay2670 ◽

Cited By ~ 7

Author(s):

S. Keihani ◽

V. Kluever ◽

S. Mandad ◽

V. Bansal ◽

R. Rahman ◽

...

Keyword(s):

Synaptic Vesicle ◽

Noncoding Rna ◽

Molecular Mechanisms ◽

Rna Binding ◽

Calcium Influx ◽

Binding Protein ◽

Synaptic Activity ◽

Vesicle Release ◽

Presynaptic Function ◽

Synaptic Vesicle Release

The cellular and the molecular mechanisms by which long noncoding RNAs (lncRNAs) may regulate presynaptic function and neuronal activity are largely unexplored. Here, we established an integrated screening strategy to discover lncRNAs implicated in neurotransmitter and synaptic vesicle release. With this approach, we identified neuroLNC, a neuron-specific nuclear lncRNA conserved from rodents to humans. NeuroLNC is tuned by synaptic activity and influences several other essential aspects of neuronal development including calcium influx, neuritogenesis, and neuronal migration in vivo. We defined the molecular interactors of neuroLNC in detail using chromatin isolation by RNA purification, RNA interactome analysis, and protein mass spectrometry. We found that the effects of neuroLNC on synaptic vesicle release require interaction with the RNA-binding protein TDP-43 (TAR DNA binding protein-43) and the selective stabilization of mRNAs encoding for presynaptic proteins. These results provide the first proof of an lncRNA that orchestrates neuronal excitability by influencing presynaptic function.

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Increased synaptic facilitation and exploratory behavior in mice lacking the presynaptic protein Mover

10.1101/560896 ◽

2019 ◽

Cited By ~ 1

Author(s):

Julio S. Viotti ◽

Frederik W. Ott ◽

Eva M. Schleicher ◽

Jannek M. Wagner ◽

Yvonne Bouter ◽

...

Keyword(s):

Synaptic Transmission ◽

Mossy Fiber ◽

Special Functions ◽

Reference Memory ◽

Specific Protein ◽

Molecular Machinery ◽

Specific Proteins ◽

Presynaptic Protein ◽

Conserved Core ◽

Presynaptic Proteins

AbstractIn vertebrates and invertebrates, neurotransmitter release relies on a highly conserved molecular machinery. A surprisingly small number of presynaptic proteins evolved specifically in vertebrates. How they expand the power or versatility of the conserved core machinery is unclear. One of these vertebrate-specific proteins, called Mover / TPRGL / SVAP30, is heterogeneously expressed throughout the brain, suggesting that it adds special functions to subtypes of presynaptic terminals. In this study we generated Mover knockout mice to investigate the role of Mover from synaptic transmission to behavior. Deletion of Mover did not affect synaptic transmission at CA3 to CA1 synapses. In contrast, Mover deficient mice had strongly increased short-term facilitation at mossy fiber to CA3 synapses. This increase included frequency facilitation, a hallmark of mossy fiber terminal function. The effect was age- and Ca2+-dependent, and relied on the Kainate receptor/cAMP pathway in the mossy fiber terminals. Despite this change in presynaptic plasticity, the absence of Mover did not affect long-term spatial reference memory or working memory, but led to reduced anxiety. These discoveries suggest that Mover has distinct roles at different synapses. At mossy-fiber terminals, it acts to constrain the extent of presynaptic facilitation. Its role in activity-dependent neurotransmission could be necessary for normal anxiety responses.Significance StatementThe enormous increase in the complexity of brains during evolution is accompanied by a remarkably small number of new, vertebrate-specific presynaptic proteins. These proteins are unlikely to be essential for transmitter release, because invertebrate synapses do not need them. But what functions do they fulfill? We show that the vertebrate-specific protein Mover is involved in constraining the release of neurotransmitters in some synapses in the hippocampus, while not affecting others. We further demonstrate that the absence of this protein leads to decreased anxiety levels. Understanding the function of such a protein can help us further understand synaptic transmission, the specializations that are brought about in vertebrate synapses, and how this can help or hinder neurological or psychiatric disorders.

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Ubiquitin C-terminal hydrolase L1 (UCH-L1) loss causes neurodegeneration by altering protein turnover in the first postnatal weeks

Proceedings of the National Academy of Sciences ◽

10.1073/pnas.1812413116 ◽

2019 ◽

Vol 116 (16) ◽

pp. 7963-7972 ◽

Cited By ~ 5

Author(s):

Anna T. Reinicke ◽

Karoline Laban ◽

Marlies Sachs ◽

Vanessa Kraus ◽

Michael Walden ◽

...

Keyword(s):

Protein Synthesis ◽

Protein Turnover ◽

Neuronal Development ◽

Postnatal Period ◽

Neuronal Function ◽

Neuronal Protein ◽

Neurological Phenotype ◽

Deficient Mice

Ubiquitin C-terminal hydrolase L1 (UCH-L1) is one of the most abundant and enigmatic enzymes of the CNS. Based on existing UCH-L1 knockout models, UCH-L1 is thought to be required for the maintenance of axonal integrity, but not for neuronal development despite its high expression in neurons. Several lines of evidence suggest a role for UCH-L1 in mUB homeostasis, although the specific in vivo substrate remains elusive. Since the precise mechanisms underlying UCH-L1–deficient neurodegeneration remain unclear, we generated a transgenic mouse model of UCH-L1 deficiency. By performing biochemical and behavioral analyses we can show that UCH-L1 deficiency causes an acceleration of sensorimotor reflex development in the first postnatal week followed by a degeneration of motor function starting at periadolescence in the setting of normal cerebral mUB levels. In the first postnatal weeks, neuronal protein synthesis and proteasomal protein degradation are enhanced, with endoplasmic reticulum stress, and energy depletion, leading to proteasomal impairment and an accumulation of nondegraded ubiquitinated protein. Increased protein turnover is associated with enhanced mTORC1 activity restricted to the postnatal period in UCH-L1–deficient brains. Inhibition of mTORC1 with rapamycin decreases protein synthesis and ubiquitin accumulation in UCH-L1–deficient neurons. Strikingly, rapamycin treatment in the first 8 postnatal days ameliorates the neurological phenotype of UCH-L1–deficient mice up to 16 weeks, suggesting that early control of protein homeostasis is imperative for long-term neuronal survival. In summary, we identified a critical presymptomatic period during which UCH-L1–dependent enhanced protein synthesis results in neuronal strain and progressive loss of neuronal function.

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mTORC1 and mTORC2 regulate distinct aspects of glutamatergic synaptic transmission

10.1101/731554 ◽

2019 ◽

Author(s):

Matthew P. McCabe ◽

Erin R. Cullen ◽

Caitlynn M. Barrows ◽

Amy N. Shore ◽

Katharine I. Tooke ◽

...

Keyword(s):

Synaptic Transmission ◽

Hippocampal Neurons ◽

Mtor Signaling ◽

Major Mechanism ◽

Presynaptic Function ◽

Glutamatergic Synaptic Transmission ◽

Presynaptic Release ◽

Neuron Growth ◽

Cell Growth And Proliferation ◽

Synaptic Vesicle Release

AbstractAlthough mTOR signaling is known as a broad regulator of cell growth and proliferation, in neurons it regulates synaptic transmission, which is thought to be a major mechanism through which altered mTOR signaling leads to neurological disease. Although previous studies have delineated postsynaptic roles for mTOR, whether it regulates presynaptic function is largely unknown. Moreover, the mTOR kinase operates in two complexes, mTORC1 and mTORC2, suggesting that mTOR’s role in synaptic transmission may be complex-specific. To better understand each complex’s role in synaptic transmission, we genetically inactivated mTORC1 or mTORC2 in cultured mouse glutamatergic hippocampal neurons. Inactivation of either complex reduced neuron growth and evoked EPSCs, however, mTORC1 exerted its effects on eEPSCs at the postsynapse and mTORC2 at the presynapse. Furthermore, inactivation of each complex altered specific modes of synaptic vesicle release, suggesting that mTORC1 and mTORC2 differentially modulate postsynaptic responsiveness and presynaptic release to optimize glutamatergic synaptic transmission.

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Effects of carbamylcholine on chick embryo aggregate retina cell cultures

Proceedings, annual meeting, Electron Microscopy Society of America ◽

10.1017/s0424820100103814 ◽

1988 ◽

Vol 46 ◽

pp. 350-351

Author(s):

Glenn M. Cohen ◽

Radharaman Ray

Keyword(s):

Cell Cultures ◽

Single Cells ◽

Retinal Cell ◽

Cell Aggregates ◽

High Concentration ◽

In Ovo ◽

Sterile Culture ◽

Retinal Tissue ◽

Synaptic Junctions ◽

And Control

Retinal,cell aggregates develop in culture in a pattern similar to the in ovo retina, forming neurites first and then synapses. In the present study, we continuously exposed chick retinal cell aggregates to a high concentration (1 mM) of carbamylcholine (carbachol), an acetylcholine (ACh) analog that resists hydrolysis by acetylcholinesterase (AChE). This situation is similar to organophosphorus anticholinesterase poisoning in which the ACh level is elevated at synaptic junctions due to inhibition of AChE, Our objective was to determine whether continuous carbachol exposure either damaged cholino- ceptive neurites, cell bodies, and synaptic elements of the aggregates or influenced (hastened or retarded) their development.The retinal tissue was isolated aseptically from 11 day embryonic White Leghorn chicks and then enzymatically (trypsin) and mechanically (trituration) dissociated into single cells. After washing the cells by repeated suspension and low (about 200 x G) centrifugation twice, aggregate cell cultures (about l0 cells/culture) were initiated in 1.5 ml medium (BME, GIBCO) in 35 mm sterile culture dishes and maintained as experimental (containing 10-3 M carbachol) and control specimens.

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The Lateral Giant Fiber to Motor Giant Fiber Synapse in Crayfish

Proceedings, annual meeting, Electron Microscopy Society of America ◽

10.1017/s0424820100094103 ◽

1972 ◽

Vol 30 ◽

pp. 170-171

Author(s):

Charles A. Stirling

Keyword(s):

Synaptic Vesicles ◽

Procambarus Clarkii ◽

Synaptic Contact ◽

Giant Fiber ◽

Synaptic Junctions

The lateral giant (LG) to motor giant (MoG) synapses in crayfish (Procambarus clarkii) abdominal ganglia are the classic electrotonic synapses. They have previously been described as having synaptic vesicles and as having them on both the pre- and postsynaptic sides of symmetrical synaptic junctions. This positioning of vesicles would make these very atypical synapses, but in the present work on the crayfish Astacus pallipes the motor giant has never been found to contain any type of vesicle at its synapses with the lateral giant fiber.The lateral to motor giant fiber synapses all occur on short branches off the main giant fibers. Closely associated with these giant fiber synapses are two small presynaptic nerves which make synaptic contact with both of the giant fibers and with their small branches.

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Synaptic organization of the gustatory NST

Proceedings, annual meeting, Electron Microscopy Society of America ◽

10.1017/s0424820100168487 ◽

1994 ◽

Vol 52 ◽

pp. 150-151

Author(s):

M. C. Whitehead

Keyword(s):

Central Nervous System ◽

Dendritic Spines ◽

Fundamental Problem ◽

Cell Types ◽

Brain Regions ◽

Excitatory Synapses ◽

Solitary Tract ◽

Synaptic Organization ◽

Synaptic Junctions ◽

Afferent Terminals

A fundamental problem in taste research is to determine how gustatory signals are processed and disseminated in the mammalian central nervous system. An important first step toward understanding information processing is the identification of cell types in the nucleus of the solitary tract (NST) and their synaptic relationships with oral primary afferent terminals. Facial and glossopharyngeal (LIX) terminals in the hamster were labelled with HRP, examined with EM, and characterized as containing moderate concentrations of medium-sized round vesicles, and engaging in asymmetrical synaptic junctions. Ultrastructurally the endings resemble excitatory synapses in other brain regions.Labelled facial afferent endings in the RC subdivision synapse almost exclusively with distal dendrites and dendritic spines of NST cells. Most synaptic relationships between the facial synapses and the dendrites are simple. However, 40% of facial endings engage in complex synaptic relationships within glomeruli containing unlabelled axon endings particularly ones termed "SP" endings. SP endings are densely packed with small, pleomorphic vesicles and synapse with both the facial endings and their postsynaptic dendrites by means of nearly symmetrical junctions.

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