. A mammalian nervous-system-specific plasma membrane proteasome complex that modulates neuronal function. Nat Struct Mol Biol. 2017 Mar 13; PubMed.

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  1. The work is amazing in scope and the diversity of methods and approaches that have been employed by the two authors and conducted experimentally only by the first author! A true tour de force. The work introduces a completely novel and unexpected potential for neurons to communicate with each other and with other cells. The discovery that in neurons a subset of proteasomes spans the plasma membrane opens the potential for the localized production of signaling peptides that are secreted via a non-vesicular mechanism. Besides the necessary confirmation of the results by other groups, the most important questions in my mind concern the nature of the peptides generated, what action(s) they have and on which cells, and whether neuronal activity could alter the amount or type of peptides—questions that the authors are raising in the discussion.

    The work represents a fantastic example of fundamental research. Whether activity of the neuronal membrane proteasome (NMP) might be good or bad for neuronal health is not yet known. So it seems a bit premature to speculate on what this fundamental discovery means for diseases. The authors have uncovered an intriguing and unexpected novel mechanism for communication by neurons. Since communication is crucial for the proper functioning of the brain, any new insight into neuronal communication does potentially bear on diseases states. In a disease state, the NMP could be blocked by misfolded proteins either from the cytoplasm or from the extracellular side. Alternatively, disease-linked modulation of the NMP activity or the types of peptides produced could have deleterious effects on neurons or other cells. It is unexpected discoveries such as the ones made in this study that are enabled by fundamental research. Fundamental research leads to a better understanding of and unexpected insights into how the brain works. Such deeper understanding has many benefits, including novel insights into disease mechanisms.

    The authors have substantiated their findings by testing them with a diverse set of techniques, each with different caveats. This softens the fact that many experiments were only done twice or three times, making traditional statistical claims questionable. I am much looking forward to an analysis of the peptides that are produced by the NMP. Knowing the identity of the peptides will go some way toward elucidating the function of the NMP. Unfortunately, the analysis of the action of the peptides is very preliminary and the calcium spikes observed in Fig 6 are not directly comparable to the sustained calcium increases in described in Fig 7. Maybe the processed peptides used in Fig 7 are distinct from the “fresh” peptides in Fig 6? Similar caution seems advised when considering whether NMDA receptors are involved in peptide action (Fig 7).

    View all comments by Felix Schweizer
  2. The authors discovered that some of the 20S proteasomes are localized by a glycoprotein sheath within the membranes of neurons; reaching out into the extracellular space. The specific transmembrane location of these 20S proteasomes allows them to degrade intracellular proteins by proteolysis and to secrete peptides into the interstitial space. The experiments show that the peptides of the proteolysed proteins regulate neuronal functions, such as synaptic transmissions and calcium signaling. The discovery of the transmembrane proteasome that secretes peptides with functional activity is, therefore, interesting for basic and medical researchers. The proteasome has been in focus in clinical research as a target for anti-cancer treatment and for Alzheimer’s and Parkinson’s diseases. Reduced activity of the proteasome has been shown to attenuate some forms of memory formation. However, with the discovery of the transmembrane proteasome, some of the conclusions drawn from previous studies might need to be re-evaluated to take the new findings into account. Thus, ongoing research has to show if the transmembrane proteasome represents a useful target to battle cellular processes of neurodegeneration.

    View all comments by Thomas Behnisch
  3. This is an interesting series of studies. First, I’ve always thought of the proteasome as a slow processor that degrades a wide variety of things in a cell. That it can act rapidly to modulate neuronal activity is interesting. But more intriguing to me is that this is another way for a cell to secrete proteins into the brain’s extracellular space, potentially in a synaptic-dependent manner. Many neurodegenerative diseases involve proteins found within the extracellular space, but in many cases we don’t know how or why they are secreted. For Aβ, we know how the peptide gets secreted and it accumulates in extracellular space, so that makes sense to some extent. But tau and α-synuclein are generally intracellular proteins that accumulate intracellularly. How those proteins are secreted into the extracellular space, and why they are there, remains largely unknown. (For that matter, why are many proteins in the extracellular space, such as GFAP?) A proteasome that links an intracellular compartment with the extracellular space could be a mechanism that eliminates these proteins from the cell. Additionally, Aβ, tau, and α-synuclein secretion are all regulated by neuronal activity. Perhaps this neuronal membrane proteasome is playing a role in synaptic-dependent secretion. Much of this above is speculation, but it is certainly fun to think about how this new proteasome function could impact neurodegenerative diseases.

    View all comments by John Cirrito
  4. Interesting and perhaps related: It has been known for some time that extracellular UPS components are present and functional (Sixt et al, 2008), including in cerebrospinal fluid (Mueller et al., 2012). This may reflect favorably on Model 2 proposed by Ramachandran and Margolis.

    References:

    . Extracellular proteasome in the human alveolar space: a new housekeeping enzyme?. Am J Physiol Lung Cell Mol Physiol. 2007 May;292(5):L1280-8. Epub 2007 Jan 12 PubMed.

    . Circulating Extracellular Proteasome in the Cerebrospinal Fluid: A Study on Concentration and Proteolytic Activity. J Mol Neurosci. 2011 Sep 1; PubMed.

    View all comments by Steve Barger

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