Abstract:Disruption of synapses underlies a plethora of neurodevelopmental and neurodegenerative disease. Presynaptic specialization called the active zone plays a critical role in the communication with postsynaptic neuron. While the role of many proteins at the active zones in synaptic communication is relatively well studied, very little is known about how these proteins are transported to the synapses. For example, are there distinct mechanisms for the transport of active zone components or are they all transported… Show more
“…At 72 hours after the induction of Par-1, there was a further decrease in EJP amplitudes while the mini EJP amplitudes remained unaltered (Fig. 3A–D ), consistent with the previous observation that neither apposition nor the intensity of DGluRIII were significantly altered in lines overexpressing Par-1 18 . It is important to note while there were some effects of the drug RU-486 on mEJP amplitudes and frequency (Supplemental Fig.…”
Section: Resultssupporting
confidence: 92%
“…2B,F ). Although we cannot rule out the role of Futsch and/or cytoskeleton at later stages, these data indicate that Futsch, similar to tau 18 is not required for the increase in BRP accumulation within axons at the initial time points. Figure 4 Futsch does not mediate accumulation of BRP within axons.…”
Section: Resultsmentioning
confidence: 65%
“…A previous study 18 revealed that elevated levels of presynaptic Par-1 lead to a selective accumulation of BRP in the axons concomitant with loss of BRP from the synapses. Since this study largely used overexpression of Par-1 as a means to increase its levels, we wondered whether physiological manipulations that lead to increased Par-1 levels would also show selective axonal accumulations of BRP.…”
Section: Resultsmentioning
confidence: 95%
“…To test whether decreased synaptic transmission 18 was an early consequence of increased accumulation of BRP within axons, we performed intracellular recordings from larvae that had just begun to accumulate BRP (~24 Hours post induction of Par-1 transgene) and time points in between until the synapses started to show a significant decrease in BRP (~72 Hours). We found that at 0 hours when accumulation of BRP within the axons is not increased significantly, the synaptic transmission (mEJP amplitude, frequency and EJP amplitudes) (Fig.…”
Section: Resultsmentioning
confidence: 99%
“…Interestingly, it was also noted that Par-1 is present in the presynaptic compartment albeit at very low levels 17 , suggesting that Par-1 may also have a role in the presynaptic compartment. It was recently demonstrated that elevated levels of presynaptic Par-1 lead to selective localization defects of BRP, with a significant accumulation of BRP within the axons and a corresponding decrease of BRP from the active zones 18 . While it is clear that the effect of increased Par-1 on localization of BRP is independent of Tau-a microtubule associated protein (MAP) and a well studied substrate of Par-1 18 – 21 , it is unclear whether other microtubule binding proteins such as Futsch (a MAP1B homolog) 22 , which has been proposed to be a likely substrate of Par-1 16 , might be involved.…”
Functional synaptic networks are compromised in many neurodevelopmental and neurodegenerative diseases. While the mechanisms of axonal transport and localization of synaptic vesicles and mitochondria are relatively well studied, little is known about the mechanisms that regulate the localization of proteins that localize to active zones. Recent finding suggests that mechanisms involved in transporting proteins destined to active zones are distinct from those that transport synaptic vesicles or mitochondria. Here we report that localization of BRP-an essential active zone scaffolding protein in Drosophila, depends on the precise balance of neuronal Par-1 kinase. Disruption of Par-1 levels leads to excess accumulation of BRP in axons at the expense of BRP at active zones. Temporal analyses demonstrate that accumulation of BRP within axons precedes the loss of synaptic function and its depletion from the active zones. Mechanistically, we find that Par-1 co-localizes with BRP and is present in the same molecular complex, raising the possibility of a novel mechanism for selective localization of BRP-like active zone scaffolding proteins. Taken together, these data suggest an intriguing possibility that mislocalization of active zone proteins like BRP might be one of the earliest signs of synapse perturbation and perhaps, synaptic networks that precede many neurological disorders.
“…At 72 hours after the induction of Par-1, there was a further decrease in EJP amplitudes while the mini EJP amplitudes remained unaltered (Fig. 3A–D ), consistent with the previous observation that neither apposition nor the intensity of DGluRIII were significantly altered in lines overexpressing Par-1 18 . It is important to note while there were some effects of the drug RU-486 on mEJP amplitudes and frequency (Supplemental Fig.…”
Section: Resultssupporting
confidence: 92%
“…2B,F ). Although we cannot rule out the role of Futsch and/or cytoskeleton at later stages, these data indicate that Futsch, similar to tau 18 is not required for the increase in BRP accumulation within axons at the initial time points. Figure 4 Futsch does not mediate accumulation of BRP within axons.…”
Section: Resultsmentioning
confidence: 65%
“…A previous study 18 revealed that elevated levels of presynaptic Par-1 lead to a selective accumulation of BRP in the axons concomitant with loss of BRP from the synapses. Since this study largely used overexpression of Par-1 as a means to increase its levels, we wondered whether physiological manipulations that lead to increased Par-1 levels would also show selective axonal accumulations of BRP.…”
Section: Resultsmentioning
confidence: 95%
“…To test whether decreased synaptic transmission 18 was an early consequence of increased accumulation of BRP within axons, we performed intracellular recordings from larvae that had just begun to accumulate BRP (~24 Hours post induction of Par-1 transgene) and time points in between until the synapses started to show a significant decrease in BRP (~72 Hours). We found that at 0 hours when accumulation of BRP within the axons is not increased significantly, the synaptic transmission (mEJP amplitude, frequency and EJP amplitudes) (Fig.…”
Section: Resultsmentioning
confidence: 99%
“…Interestingly, it was also noted that Par-1 is present in the presynaptic compartment albeit at very low levels 17 , suggesting that Par-1 may also have a role in the presynaptic compartment. It was recently demonstrated that elevated levels of presynaptic Par-1 lead to selective localization defects of BRP, with a significant accumulation of BRP within the axons and a corresponding decrease of BRP from the active zones 18 . While it is clear that the effect of increased Par-1 on localization of BRP is independent of Tau-a microtubule associated protein (MAP) and a well studied substrate of Par-1 18 – 21 , it is unclear whether other microtubule binding proteins such as Futsch (a MAP1B homolog) 22 , which has been proposed to be a likely substrate of Par-1 16 , might be involved.…”
Functional synaptic networks are compromised in many neurodevelopmental and neurodegenerative diseases. While the mechanisms of axonal transport and localization of synaptic vesicles and mitochondria are relatively well studied, little is known about the mechanisms that regulate the localization of proteins that localize to active zones. Recent finding suggests that mechanisms involved in transporting proteins destined to active zones are distinct from those that transport synaptic vesicles or mitochondria. Here we report that localization of BRP-an essential active zone scaffolding protein in Drosophila, depends on the precise balance of neuronal Par-1 kinase. Disruption of Par-1 levels leads to excess accumulation of BRP in axons at the expense of BRP at active zones. Temporal analyses demonstrate that accumulation of BRP within axons precedes the loss of synaptic function and its depletion from the active zones. Mechanistically, we find that Par-1 co-localizes with BRP and is present in the same molecular complex, raising the possibility of a novel mechanism for selective localization of BRP-like active zone scaffolding proteins. Taken together, these data suggest an intriguing possibility that mislocalization of active zone proteins like BRP might be one of the earliest signs of synapse perturbation and perhaps, synaptic networks that precede many neurological disorders.
The coordinated growth and development of synapses is critical for all aspects of neural circuit function and mutations that disrupt these processes can result in various neurological defects. Several anterograde and retrograde signaling pathways, including the canonical Bone Morphogenic Protein (BMP) pathway, regulate synaptic development in vertebrates and invertebrates. At the Drosophila larval neuromuscular junction (NMJ), the retrograde BMP pathway is a part of the machinery that controls NMJ expansion concurrent with larval growth. We sought to determine whether the conserved Hippo pathway, critical for proportional growth in other tissues, also functions in NMJ development. We found that neuronal loss of the serine‐threonine protein kinase Tao, a regulator of the Hippo signaling pathway, results in supernumerary boutons which contain a normal density of active zones. Tao is also required for proper synaptic function, as reduction of Tao results in NMJs with decreased evoked excitatory junctional potentials. Surprisingly, Tao function in NMJ growth is independent of the Hippo pathway. Instead, our experiments suggest that Tao negatively regulates BMP signaling as reduction of Tao leads to an increase in pMad levels in motor neuron nuclei and an increase in BMP target gene expression. Taken together, these results support a role for Tao as a novel inhibitor of BMP signaling in motor neurons during synaptic development and function.
SUMMARY
Neurons face unique transport challenges. They need to deliver cargo over long axonal distances and to many presynaptic nerve terminals. Rab GTPases are master regulators of vesicular traffic, but essential presynaptic Rabs have not been identified. Here, we find that Rab6, a Golgi-derived GTPase for constitutive secretion, associates with mobile axonal cargo and localizes to nerve terminals. ELKS1 is a stationary presynaptic protein with Golgin homology that binds to Rab6. Knockout and rescue experiments for ELKS1 and Rab6 establish that ELKS1 captures Rab6 cargo. The ELKS1-Rab6-capturing mechanism can be transferred to mitochondria by mistargeting ELKS1 or Rab6 to them. We conclude that nerve terminals have repurposed mechanisms from constitutive exocytosis for their highly regulated secretion. By employing Golgin-like mechanisms with anchored ELKS extending its coiled-coils to capture Rab6 cargo, they have spatially separated cargo capture from fusion. ELKS complexes connect to active zones and may mediate vesicle progression toward release sites.
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