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Developmental Biology - Liquid Phase Transition

Disorder In Brain Protein Adds To ALS & Alzheimer's

The atomic structure of protein TDP-43, is compromised in neurodegenerative conditions...

On the surface, Amyotrophic Lateral Sclerosis (ALS) and Alzheimer's disease share two common threads. (1) Both are progressive and debilitating neuro-degenerative conditions and (2) both share symptoms that progressively get worse. For the moment, neither has an effective treatment, let alone a cure.

On the molecular level, a recently identified connection between these devastating diseases could help the search for new therapies. This is explained by Jeetain Mittal, the Sam and Ruth Madrid Endowed Chair in Chemical and Biomolecular Engineering in Lehigh University's P.C. Rossin College of Engineering.
Jeetain Mittal with his collaborator Nicolas Fawzi, PhD, Brown University - are focused on the TAR DNA-binding Protein 43, or TDP-43.

TDP-43 is an essential human protein found in abundance in people living with Alzheimer's and related types of dementia, as well as those diagnosed with ALS (also known as Lou Gehrig's disease).

Their team has been awarded a $3.3 million grant from the National Institutes of Health to use their combined expertise: Fawzi in experimental research, Mittal's in computational research, to visualize atomic details of TDP-43 assembly.

Each researcher is exploring the role of post-translational modification (PTMs) in disease-associated mutations in the assembly process. They will investigate these interactions using several promising targets that prevent aggregation ot TDP-43 in cell components.

The results of Mittal and Fawzi's earlier work on TDP-43 have been published in Proceedings of the National Academy of Sciences and Structure or PNAS.
"Our previous research is only the tip of the iceberg. The next step is to take a look at the actual mutations associated with ALS and Alzheimer's and get to the bottom of how they affect the assembly of TDP-43, giving us a better understanding of what causes their malfunction.

Jeetain Mittal PhD, Department of Chemical and Biomolecular Engineering, Lehigh University, Bethlehem, Pennsylvania, USA.

A Search For Clarity Amid Disorder

TDP-43 has two sides — one end of the molecule is made up of tightly packed folded regions, while the other side is classified as intrinsically disordered region (IDR). Parts of the IDR lacks any well-defined structure. As a biophysicist, Mittal has developed simulation methods to help visualize how such proteins fold — or misfold, potentially leading to disease-related aggregations within the body.

According to Mittal, the unorganized nature of IDRs such as TDP-43 facilitates formation of membrane-less organelles within cells through a process called liquid to liquid phase separation, a phenomenon that, "has taken the biology world by storm."
"Not all that long ago, people would think about a formation of organelles, or compartments within cells, the same way we think about a building having rooms separated with walls and different functions happening in different rooms. The expectation was that information within cells and functions that take place inside of them was highly compartmentalized.

But in the past 10 or 12 years, researchers have shown that cells do not require walls or membranes to make compartments.

"With liquid-liquid phase separation, you have a well-mixed solution of biomolecules, proteins, RNA, and so forth that suddenly coalesce in these very dense, liquid-like droplets. But if something goes wrong, and they don't form properly, these granules become more solid-like and prone to aggregation."

Jeetain Mittal PhD

Mittal explains: TDP-43 is a well-known component of these granules and because of the known genetic and other links to ALS, frontotemporal dementia, and Alzheimer's disease — further study is of interest to the NIH.

The team is pursuing fundamental questions about the protein's structure through two different but complementary approaches:

• Fawzi's lab conducts highly sophisticated nuclear magnetic resonance (NMR) experiments, confirming the protein's loose, noodle-like structure through numerous readings averaged together

• Mittal's lab runs physics-based computer simulations that provide detailed spatial and time-related information and can predict how mutations to TDP-43 might affect phase behavior in the formation of membrane-less organelles — "...to really get a mechanistic sense of how each step, from atoms to molecules to single protein level connects."
"Changing just a few atoms out of hundreds or thousands within the protein can affect its function, assembly, and interactions, so having a complete picture is important. Otherwise you're working in the dark, just throwing everything at it and seeing what works. We're trying to get a better understanding so we can target our approach and guide experiments in a predictive manner."

Jeetain Mittal PhD

Related Research:
A. E. Conicella, G. L. Dignon, G. H. Zerze, H. B. Schmidt, A. M. D'Ordine, Y. C. Kim, R. Rohatgi, Y. M. Ayala, J. Mittal, N. L. Fawzi. TDP-43 ?-helical structure tunes liquid-liquid phase separation and function. Proceedings of the National Academy of Sciences 117, 5883-5894 (2020). DOI: 10.1073/pnas.1912055117

A. E. Conicella, G. H. Zerze, J. Mittal, N. L. Fawzi, ALS Mutations Disrupt Phase Separation Mediated by ?-Helical Structure in the TDP-43 Low-Complexity C-Terminal Domain. Structure 24, 1537-1549 (2016). DOI: 10.1016/j.str.2016.07.007

TDP-43 is an essential RNA-binding protein that assembles into protein inclusions in >95% of cases of amyotrophic lateral sclerosis (ALS). A partially helical region in the predominantly disordered C-terminal domain harbors several mutations associated with ALS and is important for TDP-43 function and liquid–liquid phase separation. We directly demonstrate that this helical region undergoes large structural changes upon helix–helix dimerization and that point mutations can enhance helix–helix assembly. Furthermore, we demonstrate that these point variants can be used to control the material properties of phase-separated TDP-43 constructs in cells and can enhance TDP-43 RNA-splicing function. Therefore, engineered forms of the TDP-43 helical domain could be used to control in-cell phase separation, dynamic assembly and function.

Liquid–liquid phase separation (LLPS) is involved in the formation of membraneless organelles (MLOs) associated with RNA processing. The RNA-binding protein TDP-43 is present in several MLOs, undergoes LLPS, and has been linked to the pathogenesis of amyotrophic lateral sclerosis (ALS). While some ALS-associated mutations in TDP-43 disrupt self-interaction and function, here we show that designed single mutations can enhance TDP-43 assembly and function via modulating helical structure. Using molecular simulation and NMR spectroscopy, we observe large structural changes upon dimerization of TDP-43. Two conserved glycine residues (G335 and G338) are potent inhibitors of helical extension and helix–helix interaction, which are removed in part by variants at these positions, including the ALS-associated G335D. Substitution to helix-enhancing alanine at either of these positions dramatically enhances phase separation in vitro and decreases fluidity of phase-separated TDP-43 reporter compartments in cells. Furthermore, G335A increases TDP-43 splicing function in a minigene assay. Therefore, the TDP-43 helical region serves as a short but uniquely tunable module where application of biophysical principles can precisely control assembly and function in cellular and synthetic biology applications of LLPS.

Alexander E. Conicella, Gregory L. Dignon, Gül H. Zerze, Hermann Broder Schmidt, Alexandra M. D’Ordine, Young C. Kim, Rajat Rohatgi, Yuna M. Ayala, Jeetain Mittal and Nicolas L. Fawzi.

The authors thank Mandar Naik for assistance with NMR spectroscopy and Ashley Reeb for help with tissue culture and transfection experiments. Research at Brown University was supported in part by National Institute of General Medical Sciences (NIGMS) Grant R01GM118530 (to N.L.F.), NSF Grant 1845734 (to N.L.F.), and a starter grant 17-IIP-342 from the ALS Association (to N.L.F.). A.E.C. and A.M.D. were supported in part by NIGMS training grant to the Molecular Biology, Cell Biology, and Biochemistry (MCB) graduate program at Brown University (T32GM007601). G.L.D., G.H.Z., and J.M. are supported by the US Department of Energy (DOE), Office of Science, Basic Energy Sciences, Division of Material Sciences and Engineering under Award DESC0013979 (to J.M.). Work at Stanford University was supported by grants from the NIH (DP2GM105448 and R35GM118082) to R.R. and a fellowship from the Deutsche Forschungsgemeinschaft (SCHM 3082/2-1) to H.B.S. This research is based in part on data obtained at the Brown University Structural Biology Core Facility supported by the Division of Biology and Medicine, Brown University. Use of the high-performance computing capabilities of the Extreme Science and Engineering Discovery Environment, which is supported by NSF Grant TG-MCB-120014, is gratefully acknowledged in addition to resources of the National Energy Research Scientific Computing Center, a DOE Office of Science User Facility supported by the Office of Science of the US Department of Energy under Contract DE-AC02-05CH11231. The content is solely the responsibility of the authors and does not necessarily represent the official views of the funding agencies.

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Jul 16 2020   Fetal Timeline   Maternal Timeline   News

Arrows point to aggregates of TDP-43 found in the brain in this simulated TDP-43 formation of helix to helix contacts (MAGENTA). CREDIT: Proceedings of the National Academy of Sciences USA.

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