2022年度年次報告

FY2022 Annual Report

Molecular Neuroscience Unit
Assistant Professor Marco Terenzio

 

• (From left to right) Lower row: Sandra De La Fuente, Sarah Zakhia, Lokesh Agrawal, Akiko Guzman. Upper row: Maria Fernanda Bolanos Alejos, Susan Boerner, Fregoso Fernandez Esteban Gabriel, Emad El-Agamy Abdelaal, Maria Fransiska Emily, Laurent Guillaud, Marco Terenzio.

Abstract

In 2022 we have developed fibrous scaffolds using biodegradable and biocompatible compounds, which we have filed a patent in 2021 for and published. On the biological side, we continued our investigation of both axonal translation after injury and the mechanism underlying axonal degeneration in ALS using human iPSC. We have also organized an in-person workshop on axonal degeneration and regeneration. 

1. Staff

• Assistant Professor Marco Terenzio, Unit Leader

• Dr. Laurent Guillaud, Group Leader
• Dr. Lokesh Agrawal, Post-doctoral Scholar
• Dr. Madeleine Le Coz, Post-doctoral Scholar
• Dr. Sandra De La Fuente, Post-doctoral Scholar
• Sara Emad El-Agamy Abdelaal, Ph.D. Student
• Maria Fransiska Emily, Ph.D. Student
• Sarah Zakhia, Ph.D. Student
• Maria Fernanda Bolanos Alejos, Ph.D. Student
• Fregoso Fernandez Esteban Gabriel, Ph.D. Student
• Alessandro Massaro, Research Intern (May-August 2022)
• Yang Ming, Rotation Student (May-August 2022)
• Tara Helmi Turkki, Rotation Student (May-August 2022)
• Ayane Mitoro, Research Intern, (September-October 2022)
• Sophie Elizabeth Field, Research Intern (October 2022-March 2023)
• Akiko Guzman, Research Unit Administrator

2. Collaborations

2.1 Local Translation and axonal dysfunction in Amyotrophic Lateral Sclerosis

• Type of collaboration: Joint research
• Researchers:
  • Professor Andrea Malaspina, UCL, UK

2.2 Local axonal and synaptic maintenance mechanisms in a Drosophila model of Wallerian degeneration

• Type of collaboration: Joint research
• Researchers:
  • Assistant Professor Lukas Neukomm, University of Lausanne, Switzerland
  • Maria Paglione, Ph.D. student

2.3 Using nanographene compounds for imaging in neurons

• Type of collaboration: Joint research
• Researcher:
  • Assistant Professor Akimitsu Narita, OIST

 

3. Activities and Findings

Neurons are extremely polarized cells with axons that can extend up to one meter in length. Hence the need to tightly regulate the flux of information from the periphery to the center. Indeed, axonal transport defects of a variety of peripheral signaling complexes, including endosomes, mitochondria and mRNP granules, have been shown to result in neuronal degeneration. Axonal protein synthesis has also been connected to the transmission of both regenerative and neurodegenerative signals. Our lab focuses on the understanding of the mechanisms underlying the correct localization of signaling complexes by molecular transport and/or local protein synthesis and how this affects neuronal homeostasis, regeneration, and degeneration. To this extent, we have continued lines of research.

1. Contribution of axonal transport and translation to nerve regeneration. Axonal injuries are known to trigger axonal mRNA translation. We designed microfluidics chambers (MFCs) to separate the axonal network from the neuronal cell bodies, enabling the study of axons in isolation (Emily et al, 2022). Taking advantage of this system, we characterized the kinetics of bulk axonal translation and retrograde transport of translated proteins. We have compared different stimuli, such as growth factors, for their ability to enhance local translation. We are now in the process of finalizing a modified version of a MFC, which will enable to perform axonal injury in a control environment to allow for the study of translation after injury.

 

2. Design of nanomaterial scaffolds to aid nerve regeneration. We investigated the effects of finely controlled fiber geometry in the promotion of axonal vectorial growth by printing 3D scaffold using 2-photon lithography in collaboration with the Nanofabrication Unit at OIST. We designed a new polymer formulation to produce 3D nanofiber biodegradable and electrically conductive scaffolds to promote nerve regeneration, which we have published (Agrawal et al, 2022).

 

3. Mechanisms of axonal pathology in neurodegenerative diseases. We described how genetic depletion of Dynlrb1, a small subunit of the Dynein complex is critical for neuronal survival. We followed up this study with a proteomic screening for interactors and we discover the Fragile X mental retardation protein (FMRP) as a Dynein binding partner. Genetic depletion of Dynlrb1 causes FMRP granules accumulation and an inhibition of translation of mRNA bound to FMRP. We have also acquired a collection of human inducible pluripotent stem cells (hiPSCs) from control individuals and Amyotrophic Lateral Sclerosis (ALS) patients. Using this system, we have documented how TDP-43 pathological aggregates, a hallmark of ALS, depend on mitochondrial activity in ALS.

4. Publications

4.1 Journals

1. Biodegradable and Electrically Conductive Melanin-Poly (3-Hydroxybutyrate) 3D Fibrous Scaffolds for Neural Tissue Engineering Applications. Agrawal L, Vimal SK, Barzaghi P, Shiga T, Terenzio M.Macromol Biosci. 2022 Sep 17:e2200315.

4.2 Books and other one-time publications

1. Use of Microfluidics Chambers to Image Axonal transport in Adult Sensory Neurons. M. F. Emily , L. Agrawal , P. Barzaghi, M. Otsuki , M. Terenzio. Methods Mol Biol. 2022;2431:271-288.

4.3 Oral and Poster Presentations

Scientific Talks

1. “Dynein Roadblock 1 mediates axonal transport and degradation of FMRP1 in sensory neurons”. Invited talk at the “Mechanisms of neuronal remodelling” EMBO workshop, 11-14 March 2023, Israel. Presented by Marco Terenzio.
2. “Dynein-FMRP interaction is critical for FMRP granules motility and clearance in neurons” at the Ajou University School of Medicine (Korea) – OIST Joint Seminar, 7 March 2023. Presented by Marco Terenzio.

1. “Dynein Roadblock 1 mediates axonal transport and degradation of FMRP1 in sensory neurons”. Invited talk via Zoom at Turin University, Italy, 25^th November 2022.

3. “Dynein dynamics and signaling in neuronal survival and regeneration”. ADR2022, OIST, 3-7 October 2022. Presented by Marco Terenzio.

2. “Nicotinamide mononucleotide rescues ALS pathological phenotypes in TDP- 43N390D human iPSC-derived motor neurons”. Given by Laurent Guillaud at the ADR2022, OIST, 3-7 October 2022.

Poster Presentations:

4. “Roadblock1 regulates FMRP function by promoting its degradation” Japan Neuroscience Society meeting, July 2^nd, 2022. “Roadblock1 regulates FMRP function by promoting its degradation” Japan Neuroscience Society meeting, July 2nd, 2022. Presented by Sara Emad El-Agamy Abdelaal.
5. “Development of 3D culture scaffolds for directional neuronal growth”. Japan Neuroscience Society meeting, July 2nd, 2022. Presented by Marco Terenzio.
6. “Roadblock1 regulates FMRP dynamics and function” Society for neuroscience meeting, USA. November 15^th, 2022. Presented by Sara Emad El-Agamy Abdelaal.

 

5. Intellectual Property Rights and Other Specific Achievements

6. Meetings and Events

We organized the Axonal Degeneration and Regeneration Workshop at OIST (ADR2022): https://groups.oist.jp/adr 

7. Other

7.1 Teaching

• Title: Neuronal Molecular Signaling
• Curriculum: Course A361 by Prof. Marco Terenzio.
• Date: Term 3 2022
• Venue: OIST campus.
• Lecturer: Marco Terenzio