Waste-Management Protein Implicated in Neurogenerative Diseases

A collaborative study led by Columbia University has identified a new fibril in diseased brains that is formed by a protein normally tasked with clearing molecular debris. The “surprising and provocative result” has potential bearing on understanding of neurogenerative diseases, according to co-first author Andrew Chang.

The team found that TMEM106B—a core component of lysosomes and endosomes that clean up the junk that accumulates in cells as we age—can form fibrils, behavior was previously unknown. Normally, TMEM106B spans the membranes of those waste-management organelles, but the study found that it can split into two fragments. Fragments inside the organelles can then self-assemble into what the researchers suspect could be cell-hobbling fibrils. 

To make this discovery, the researchers first extracted proteins from brain tissue donated by 11 patients who had died from three neurodegenerative diseases associated with misfolded proteins: progressive supranuclear palsy (PSP)., dementia with Lewy bodies (DLB) and frontotemporal lobar degeneration (FTLD).

With a cryogenic electron microscope (cryo-EM), the team took snapshots of individual protein molecules at many different angles. From these, the researchers constructed three-dimensional models of the protein in atomic detail. Those models, in turn, helped the researchers identify TMEM106B by making educated guesses about the exact sequence of the protein’s amino-acid building blocks.

The researchers fully expected that one of the long-known fibril-forming proteins, such as the tau protein in Alzheimer’s disease, would end up matching with the models from the cryo-EM data. Instead, the matching exercise delivered a surprising result: the mysterious protein matched a 135-amino-acid fragment of TMEM106B. That was an exciting revelation because this same protein was identified more than a decade ago in a broad hunt for genes potentially associated with FTLD.

So far, the data in hand shows only that TMEM106B fibrils are present in diseased brain tissue, not that the fibrils cause the diseases. Still, the prevalence of TMEM106B fibrils in tissue from different brain diseases, combined with the protein’s normal place in lysosomes and endosomes, points toward a possible disease-causing role, says Anthony Fitzpatrick, PhD, principal investigator at Columbia’s Zuckerman Institute.

Their work, published recently in Cell, posits that the formation of TMEM106B fibrils disrupts lysosome function, which, in turn, promotes the formation of fibrils made of other known fibril-forming proteins. These malfunctions could kill brain cells, leading to dementia, movement problems, speech pathologies and other symptoms of Alzheimer’s, PSP, FTLD and other brain diseases with telltale protein tangles. “We now have a promising new lead,” said Dr. Fitzpatrick. “It could point towards a common thread linking a range of neurodegenerative diseases and could open the way to new interventions.”