Piccolo and Bassoon

Introduction to Piccolo and Bassoon

Piccolo is a cytomatrix protein that plays an important role in recruiting and integrating the intracellular endocytosis and exocytosis-related molecules in synaptic vesicles. Meanwhile, pilot studies have suggested that it is involved in the production of presynaptic F-actin and is associated with the deposition of presynaptic proteins. Analysis of its primary structure on rats has revealed that piccolo consists of a glutamine-rich heptad repeat domain, zinc finger, coiled-coil domain, proline-rich sequence domain, as well as C2 domain. Furthermore, many reports have shown that piccolo is sharing with a similar structure to the presynaptic cytoskeletal matrix protein, bassoon. Both proteins are found to be critical for the regulation of different activities among presynaptic, neuronal nucleus, and neuronal cells.

Fig.1 Structures of Piccolo and Bassoon. (Mukherjee, 2010)

Piccolo and Bassoon in Synaptic Vesicle

Piccolo and bassoon are multi-domain proteins with a size of approximately 420 kDa that exists at the active zone of neurotransmitter release. Piccolo is closely related to the presynaptic cytoskeletal matrix, but extremely difficult to extract. Moreover, recent studies have indicated that piccolo and bassoon are key components of synaptic vesicle cycling. Besides, researchers have demonstrated that mutations or loss of bassoon and piccolo can cause abnormal expression of several presynaptic proteins, which eventually leads to synaptic dysfunction. As a result, piccolo and bassoon have been linked to a wide variety of neurological disorders, such as Alzheimer’s disease and major depression.

Fig.2 Piccolo/Bassoon as key regulators of presynaptic protein turnover. (Kononenko, 2013)

Recently, many attempts have been made to generate genetic knockout models of piccolo or bassoon. For example, mice lacking the central region of bassoon have been established to show major structural defects in the zonal synapses of the retina and cochlea, which includes the abnormal aggregation of voltage-gated calcium channels and abnormal separation of ribbon from presynaptic membrane. Also, they showed enhanced short-term depression and a high proportion of silent synapses. In the present studies of piccolo-deficient neurons, an RNAi knockdown model of piccolo has been proven its significant role in the enhancement of activity-dependent synaptic vesicle exocytosis and presynaptic synapsin1a diffusion. Specifically, bassoon/piccolo double knockdown (DKD) models have also shown promising results in maintaining synaptic integrity. Numerous data have suggested that this process can be regulated by the binding of bassoon and piccolo zinc finger domains to E3 ubiquitin ligase Siah1.

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References

1. Mukherjee, K.; et al. Piccolo and bassoon maintain synaptic vesicle clustering without directly participating in vesicle exocytosis. Proceedings of the National Academy of Sciences. 2010, 107(14): 6504-6509.
2. Kononenko, N.; et al. Synaptic requiem: a duet for Piccolo and Bassoon. The EMBO journal. 2013, 32(7): 920-922.