Schattling B, Engler JB, Volkmann C, Rothammer N, Woo MS, Petersen M, Winkler I, Kaufmann M, Rosenkranz SC, Fejtova A, Thomas U, Bose A, Bauer S, Träger S, Miller KK, Brück W, Duncan KE, Salinas G, Soba P, Gundelfinger ED, Merkler D, Friese MA. Nat Neurosci. 2019 Apr 22. doi: 10.1038/s41593-019-0385-4. [Epub ahead of print]
Multiple sclerosis (MS) is characterized by inflammatory insults that drive neuroaxonal injury. However, knowledge about neuron-intrinsic responses to inflammation is limited. By leveraging neuron-specific messenger RNA profiling, we found that neuroinflammation leads to induction and toxic accumulation of the synaptic protein bassoon (Bsn) in the neuronal somata of mice and patients with MS. Neuronal overexpression of Bsn in flies resulted in reduction of lifespan, while genetic disruption of Bsn protected mice from inflammation-induced neuroaxonal injury. Notably, pharmacological proteasome activation boosted the clearance of accumulated Bsn and enhanced neuronal survival. Our study demonstrates that neuroinflammation initiates toxic protein accumulation in neuronal somata and advocates proteasome activation as a potential remedy
The active zone or synaptic active zone is a term used to define the site of neurotransmitter release. Two neurons make near contact through structures called synapses allowing them to communicate with each other. As synapse consists of the presynaptic bouton of one neuron which stores vesicles containing neurotransmitter and a second, postsynaptic neuron which bears receptors for the neurotransmitter, together with a gap between the two called the synaptic cleft (with synaptic adhesion molecules, SAMs, holding the two together. When an action potential reaches the presynaptic bouton, the contents of the vesicles are released into the synaptic cleft and the released neurotransmitter travels across the cleft to the postsynaptic neuron and activates the receptors on the postsynaptic membrane.
The active zone is the region in the presynaptic bouton that mediates neurotransmitter release and is composed of the presynaptic membrane and a dense collection of proteins including bassoon and piccolo. The function of the active zone is to ensure that neurotransmitters can be reliably released in a specific location of a neuron and only released when the neuron fires an action potential. As an action potential propagates down an axon it reaches the axon terminal called the presynaptic bouton. In the presynaptic bouton, the action potential activates calcium channels (VDCC) that cause a local influx of calcium. The increase in calcium is detected by proteins in the active zone and forces vesicles containing neurotransmitter to fuse with the membrane. This fusion of the vesicles with the membrane releases the neurotransmitters into the synaptic cleft (space between the presynaptic bouton and the postsynaptic membrane). The neurotransmitters then diffuse across the cleft and bind to ligand gated ion channels and G-protein coupled receptors on the postsynaptic membrane. The binding of neurotransmitters to the postsynaptic receptors then induces a change in the postsynaptic neuron. The process of releasing neurotransmitters and binding to the postsynaptic receptors to cause a change in the postsynaptic neuron is called neurotransmission.
Bassoon is a protein that is link to piccilo and this is associated with voltage dependent calcium channels (VDCC). Loss of Bassoon and Piccolo apparently leads to the aberrant degradation of multiple presynaptic proteins, culminating in synapse degeneration.
In this paper they find an accumulation of Bassoon and this is linked with nerve damage and suggest that we should use a cell content vaccuum cleaner, a proteosome activator, and that going to be a good thing.
This is an interesting one as ProfG and NDG have planned to do a trial on the use of proteosome inhibitor, with a view of targeting the plasma cells, so will it be a bad thing? Again it shows us that biology is not simple. We were planning on doing some beasty studies first but got the chop, it seems now it would be a good idea to see if something is going to happen.
In this study they focus on a nerve called a motor nerve and these are lost in motor neuron disease and some go in EAE. They show that this bassoon protein is highly expressed in motor nerves in EAE and MS. However, on a quick look in the data bases and this protein is every where as it should be because where you have the nerve bodies, you have synapses. In the paper the bassoon is in the cytoplasm (the black hole is the nucleus) in MS (it looks like it in the nucleus). However one question is how does inflammation that is largely in the white matter in EAE affect the motor nerve in the grey matter.