Canadian Consortium’s 100th publication reports new findings about a key protein in inherited form of dementia and ALS – will be a milestone in more ways than one

A research team within the Canadian Consortium on Neurodegeneration in Aging (CCNA) has reached a major milestone. Their recent publication – marking the CCNA’s 100th – reveals significant information about an important protein that goes awry in the early stages of Frontotemporal Lobar Degeneration and Amyotropic Lateral Sclerosis.

When we are well, we tend to underestimate the complexity of the vast number of events – at the levels of molecules, subcellular organelles, cells, and the entire organism – that make our thoughts and actions seem so simple. The appearance of disease, however, unmasks just how complex even the simplest acts of thinking and purposeful movement can be. This is nowhere more true than in diseases affecting the nervous system.

As it turns out, two dreaded disease states – Amyotrophic Lateral Sclerosis (ALS) and Frontotemporal Lobar Degeneration (FTLD) – share a common disruption of a specific protein which accompanies (and in inherited forms of the illnesses, might even cause) the inability to control movement or thinking.

The specific protein involved is referred to as “FUS” (i.e., fused in sarcoma). While this is a small protein, it has significant effects – particularly in nerve cells where it is active both in the nucleus, where it regulates transcription of DNA into RNA, and at the ends of nerves and their branches, where it regulates translation of RNA into proteins. There is a strong sense that FUS is essential to how neurons communicate.

This hearkens back to a breakthrough of the last century – “DNA makes RNA and RNA makes protein” – that is now learned by school children. These days, breakthroughs come from understanding just how all of this happens. In the case of RNA making protein, the protein must get to where it is required and there remain active. This is where FUS comes in. For it to transport RNA, FUS itself must be able to change its shapes and functional states. Alternatively, the inability of FUS to appropriately change its shapes and functions (e.g., from non-functional long strings of beads into functional droplets and gels) appears to be responsible for their discovered role in ALS and FTLD.

Exactly how this happens has been revealed in a series of elegant experiments conducted by an international team headed by Prof. Peter St George-Hyslop (University of Toronto), in collaboration with several colleagues at the University of Cambridge, and in the United States of America and Spain.

Prof. St George-Hyslop’s CCNA-supported findings (including a post-doctoral award to one of the two co-lead authors) were reported this month in the prestigious journal, Cell. There, the team articulated a key role for FUS and how abnormal changes in its shapes and functions are associated with the development of ALS and FTLD. In doing so, they covered specific mechanisms of involvement of FUS in the disease process, which had been unknown and are now are implicated in these diseases.

Like all good science, the new work opens many more questions about just how this disordered state results in more widespread changes, and how these might be preempted. Intriguingly, the team identified a means of rescuing the impaired protein synthesis in specific parts of a nerve cell.

This work points to a common final mechanism for FUS-related neurodegenerative diseases. This is an essential step in the long path to understanding how this could be used therapeutically. An arduous journey to be sure, but thanks to this work, we can move forward.

This is but a sample of the productivity of CCNA researchers that has been published to date. Be sure to regularly visit our ever-growing publications database which is anticipated to grow significantly as COMPASS-ND data becomes readily available to CCNA researchers. To find out more about this impactful work, contact the lead of Team 1, Peter St George Hyslop directly by clicking here.