The good, the bad and their equilibrium: New insight in protein aggregation in neurons and new possible pathways for medical treatment

Protein

UZH-researcher discovered that good protein aggregations are in a dynamic equilibrium with pathological ones and preventing them to take over.

Amyotrophic lateral sclerosis (ALS) and frontotemporal dementia (FTD) are two diseases with devastating consequences for patients and their families. ALS and FTD patients often live normal lives for several decades. When the disease strikes, it is so subtle that it frequently escapes diagnosis. ALS patients may first experience difficulty in walking, talking, performing fine motor tasks, or even breathing. In most cases, the disease progresses rapidly, leading to paralysis and death, typically within 1–5 years from diagnosis.

ALS directly affects the nerve cells that control most voluntary movements (also called motor neurons) and was traditionally thought to spare cognitive functions. Discoveries of the past decade, however, have made a definitive link between ALS and FTD, the most common type of dementia in populations below 60 years of age. FTD patients experience variable behavioral dysfunctions that ultimately result in the inability to think and speak, eventually leading to death 5–10 years post-diagnosis. Both ALS and FTD remain incurable, without any effective therapy to alter disease course. In fact, it is still unknown what makes the respective neurons deteriorating over the course of these diseases.

Sick neurons accumulate protein aggregates

It is known however, that sick neurons of ALS and FTD patients accumulate protein aggregates inside them, which seem to interfere with their normal function. The most important protein found in these aggregates is called TDP-43, whose physiological function is essential for the survival of most cells including neurons. Yet, how these TDP-43 inclusions form is still a mystery. 

A new study led by Tariq Afroz from the lab of Magdalini Polymenidou now shows that the essential physiological function of TDP-43 can only be performed when the protein forms a different kind of “clump”; an ordered and dynamic assembly (or an oligomer), whose exact structure is described for the first time in atomic resolution by the team that includes the structural biology groups of Frederic Allain (ETH), Peer Mittl (UZH) and Andreas Plueckthun (UZH). Importantly, the work showed that these physiological polymeric TDP-43 assemblies are in dynamic equilibrium with the pathological aggregates that directly lead to neuronal loss in ALS and FTD.

A new perception of protein aggregations in neurons

Using the molecular information obtained from their structure, the team showed that blocking the physiological TDP-43 oligomerization disrupts this equilibrium and results in increased pathologic aggregation. This result is surprising and exciting. Surprising because in most neurodegenerative diseases caused by protein aggregates, oligomers are viewed as the precursors of aggregation and often the most toxic species. In contrast, these TDP-43 oligomers are physiological and antagonize the formation of pathologic assemblies. And exciting, because the discovery points to a novel pathway for blocking TDP-43 aggregation, which can lead to novel therapies for these fatal diseases. 

Further reading

Tariq Afroz, Eva-Maria Hock, Patrick Ernst, Chiara Foglieni, Melanie Jambeau, Larissa A.B. Gilhespy,Florent Laferriere, Zuzanna Maniecka, Andreas Plückthun, Peer Mittl, Paolo Paganetti, Frédéric H.T. Allain4 & Magdalini PolymenidouFunctional and dynamic polymerization of the ALSlinkedprotein TDP-43 antagonizes its pathologicaggregation, Nature communications 8  | DOI: 10.1038/s41467-017-00062-0 www.nature.com/naturecommunications

 

Contact:

University of Zurich
Prof. Magdalini Polymenidou
Institute of Molecular Life Sciences
Winterthurerstrasse 190
CH-8057 Zürich
Phone +41 44 635 31 06
Email magdalini.polymenidou(at)imls.uzh.ch


 

Calista Fischer

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