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The Unusual Suspects in Neurodegeneration: Role of Non-Proteinogenic Amino Acids
The workshop brought scientists working in diverse scientific fields including toxicology, analytical chemistry, molecular biology, biochemistry, biophysics and neurobiology together to explore the overlap between these approaches, and to accumulate knowledge, with respect to understanding the emerging role and possible mechanisms of NPAA toxicity in neurodegeneration. Around 19 scientists attended the workshop. Participants and speakers were both experts in their fields, as well as young scientists. The workshop was a great success. Several new contacts and collaborations were established, and these otherwise disparate communities significantly benefited, finding remarkably common interests and shared goals and opportunities, and are looking forward for future joint meetings. Proceedings of the workshop will be published as part of a special issue in the MDPI journal, Toxins, focused on the topic of NPAAs and neurodegeneration, as well as toxic amino acids more generally. In addition, review article summarizing the outcomes of this meeting is currently under preparation (to be featured in this special issue), and will serve as a basis for establishing a work plan, as well as foundation for a long-term consortium for future research collaboration, as well as possible funding opportunities.
The aim of the workshop was to explore current evidences that non-proteinogenic amino acids (NPAAs), including both environmentally derived and endogenously formed representative, contribute to neurodegeneration. Although several lines of evidence support this notion, several remaining key questions were discussed during the workshop, including (1) how diverse and widespread are the NPAAs in the biological world; (2) what are the main mechanisms whereby NPAAs may contribute to neurodegeneration; and (3) more generally, what is the current state of knowledge that supports a contribution of NPAAs to neurodegeneration?
The workshop triggered lively discussions, particularly as part of both scheduled discussion sessions, and open discussion during and following lecture presentations, and also stimulated potential for new collaborations. The diversity and fundamental role of the NPAAs were both critically discussed. With respect to the first question (i.e., “how diverse and widespread are NPAAs”), one important focus was conflicting reports on how widespread and abundant NPAAs are in the environment; although some previous reports have found them commonly among various sources, others suggest they are not as widespread, and likewise, the relevance of concentrations of NPAAs in the environment, relative to the levels required for toxicity and/or meaningful to neurodegenerative effects, remain unclear. Similarly, as to the second question (i.e., “what are the main mechanisms”) although several studies have presented seemingly clear mechanisms of toxicity for NPAAs (e.g., misincorporation into proteins, and consequences thereof), considerable disagreement in this regard remains. Accordingly, one of the main outcomes was a questioning of the current state of knowledge, and need for rigorous and interdisciplinary collaboration to establish definitive information regarding both presence/abundance and mechanisms of NPAAs. The workshop, thereby, allowed discussion of how to exploit different techniques and expertise to address these lingering questions toward a unified picture of the contribution of NPAAs to neurodegeneration (or lack thereof). On this note, the consensus of participants was that a second (and likely larger) follow-up workshop/symposium on the topic would be very useful; tentatively, the organizers and participants propose a workshop within 2 years, and specifically are targeting the larger (Oort) venue of the Lorentz Center for Spring 2018.
Although much of the workshop focused on the gaps and/or discrepancies in the current body of knowledge regarding NPAAs and neurodegeneration, and challenges and opportunities with respect to addressing these gaps/discrepancies, one presentation perhaps stands out as as potentially major contribution. A presentation by one of the young investigators (Upasana Roy) on the novel use of NMR-based methods for in vivo investigation of the effects of the otherwise well studied NPAAs, -methylamino-L-alanine (BMAA), specifically in the zebrafish embryo as a model of development (including neuronal/CNS development). This study, and the results presented, gave an exciting “bird’s eye view” of the effects of this NPAA, and possible glimpse at a unifying model of the neurodevelopmental toxicity of this particular compound, and additionally elucidated previously unseen effects on lipid metabolism as it potentially relates to neurodegeneration. As such it not only provided a potential breakthrough, it also perhaps qualifies as one of the “Aha moments” (as discussed below) in the workshop.
Most of the participants realized that the exchange between scientists of the diverse communities, and different approaches is very valuable, as many problems and ultimate targets are similar. That said, several aspects covered in the workshop arguably represented qualified moments of realization and/or clarity (i.e., “Aha moments”) with respect to NPAAs and neurodegeneration owing to either fresh perspectives, or novel approaches which shed new light on the topic. Inclusion of experts in the field of protein translation (Dr. Ita Gruic-Solvaj and Dr. Mark Safro), and specifically aminoacyl tRNA synthetase - and associated proofreading mechanisms, etc. as it relates to fidelity of amino acid incorporation into proteins - provided an eye-opening view of the potential for non-canonical amino acids to be erroneously incorporated into proteins. Whereas most studies of NPAA have investigated toxic consequences in vitro and/or in cellular or animal, contributions by these experts in the fields of biochemistry/molecular biology elucidated the potential for a mechanism whereby NPAA may slip through tRNA charging/proofreading during translation, and be consequently misincorporated (as demonstrated in vitro, and in cellular systems). Likewise presentations, and associated discussion, on formation of, and methods to study, amyloid proteins/plaques (e.g., Dr. Martina Huber, Dr. Stefan Rossner) gave a clearly fundamental, but often overlooked, perspective on the potential for NPAAs to contribute to neurodegeneration. Similarly, presentation of results based on novel approaches, likewise, broadened the view of the potential for NPAA to contribute to neurodegeneration. As mentioned above, notable among these was a presentation on the use of NMR-based methods of in vivo evaluation of NPAA, and specifically metabolomics associated with BMAA exposure in the zebrafish. In addition, however, the inclusion of biophysicists (i.e., Dr. Daniel Huster, Alexander Korn) who have utilized a novel approach of synthesis, and subsequent analysis/modeling, of BMAA-containing amyloid beta (A) peptides, likewise, provided a potential new route to investigate this proposed phenomenon.
The advice of the Lorentz Center was very helpful. In particular, we were suggested to give more room for free discussions, and for involvement of younger scientists. Both worked out very nicely. The one comment might be that, in our experience, some of the UNPLANNED “breakout” discussions were perhaps even more effective than the scheduling of discussion sessions, particularly perhaps when these sessions were scheduled at times later than presentations (when participants minds were more focused on the topic).
We are very thankful to the staff of the Lorentz Center for their expert handing of all administrative matters. The workshop was a joy to organize with such cheerfully reliable support. The meeting would not have been possible without the Center’s generous financial support for which we are also most grateful.
Proceedings of the workshop will be specifically featured as part of a special issue in the MDPI journal, Toxins, focused on the topic of NPAAs and neurodegeneration. This will include a review article, to be prepared collectively by several of the invited participants, that will serve as both an “executive summary” of the workshop, as well as comprehensive review of the state of the science. In addition, it is very likely that several of the “invited” contributions this special issue will include previously unpublished relevant results from participants, and moreover, hopefully serve to attract other (who did not participate) to this topic.
A. Alia, Leiden University/Leipzig University
John Berry, Miami, Florida
Daniel Huster, Leipzig University
Kenneth Rodger, University of Sydney