The regulated release of neurotransmitters occurs via the fusion of synaptic vesicles (SVs) at specialized regions of the presynaptic membrane called the active zone (AZ). This region is defined by a cytoskeletal matrix that is assembled at AZs (CAZ), where it directs SVs towards docking and fusion sites and supports their maturation into the readily-releasable pool. In addition CAZ proteins also localize voltage-gated Ca2+-channels in close proximity to SV release sites, bringing the fusion machinery close to the calcium source. Proteins of the CAZ therefore ensure that the vesicle fusion process is temporally and spatially organized, allowing for the precise and reliable release of neurotransmission (Fig. 1).
Importantly, AZs are highly dynamic structures, supporting presynaptic remodeling, changes in neurotransmitter release efficiency, and thus presynaptic forms of plasticity. Unfortunately, this places a huge metabolic demand on neurons as they strive to maintain synaptic protein repertieurs at great distance from the cells. To cope with these challenges, neurons have developed an array of cellular programs that monitor and control not only the biosynthesis, but also the degradation of synaptic proteins. Emerging data indicate that some of these are physically situated within presynaptic and postsynaptic compartments, allowing a local control and thus a balance of synaptic proteostasis. However, it is increasingly appreciated that this flexibility comes with a prices and appears also make synapses and thus neurons susceptible to environmental and genetics insults, which contribute to both neurodevelopmental and neurodegenerative disorders (Fig. 2).
Within project A18, we are interested in understanding how presynaptic CAZ proteins regulate synaptic proteostasis. Specifically our studies are focus on the roles played by two AZ proteins, Piccolo and Bassoons. These molecules have not only been found to locally regulate synaptic transmission, but the integrity of synapses. Emerging data indicate that they locally control synaptic proteostasis and thus synapse integrity by scaffolding component of the ubiquitin, proteasome and endolysosomal systems. To test this hypothesis, we are using a combination of biochemical, molecular and cellular approaches to identify these binding partners and assess their contribution to the maintenance and clearance of SV proteins, as well as the structural integrity of synaptic junctions. Long-term, it is anticipated that these studies will help explain how and why synapses lose their capacity to clear unwanted proteins and thus contribute to neurodegenerative disorders such as Alzheimer’s and Parkinson’s disease.
Gundelfinger, E. D., Reissner, C. and C.C.Garner, Role of Bassoon and Piccolo in assembly and molecular organization of the active zone. Frontiers in Synaptic Neurosci. (2016) in press.
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Maas C., V.I. Torres, S. Leal-Ortiz, R. Terry-Lorenzo, E.D. Gundelfinger, and C.C. Garner. 2012. Bassoon and Piccolo are necessary for the proper formation of their own transport vesicle at the trans-golgi network. Journal of Neuroscience. 32:11095-108.
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Leal-Ortiz, S., C.L. Waites, R. Terry-Lorenzo, P. Zamorano, E.D. Gundelfinger, and C.C. Garner 2008. Piccolo modulation of synapsin1a dynamics regulates synaptic vesicle exocytosis.” The Journal of Cell Biology. 181:831-846.
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