An existing antiparasitic drug could offer a new way to treat dementia by acting on structures in brain cells that control protein production.
Researchers at the University of California San Diego and the University of Pittsburgh found that targeting nuclear speckles – small structures inside cell nuclei that help control how proteins are made, folded and broken down – could slow diseases caused by abnormal protein build-up in the brain.
The Pittsburgh team identified the pinworm treatment pyrvinium pamoate and demonstrated its potential for targeting nuclear speckles in a petri dish.
UC San Diego researchers then tested it in living models of neurodegenerative diseases and found it restored normal function without causing cellular stress or toxicity.
The drug cut harmful tau protein levels by about 70 per cent in mouse neurons.
Tau build-up is linked to Alzheimer’s, Parkinson’s and other tauopathies – conditions caused by excess or misfolded tau protein in the brain.
Xu Chen is associate professor in the department of neurosciences at UC San Diego School of Medicine.
The researcher said: “These are some of the most promising results I’ve seen in my whole career.
“Tauopathies are devastating diseases, and we are in desperate need of new treatments. This is a tremendous step in the right direction.”
The team also found that human neurons carrying a frontotemporal dementia-associated tau mutation had misshapen nuclear speckles and elevated tau levels.
Low doses of the drug restored nuclear speckle shape and greatly reduced the harmful protein.
Pyrvinium pamoate also showed potential for treating retinitis pigmentosa, an inherited eye disease in which a key protein in the eye’s rod cells is misfolded, causing progressive vision loss.
Senior author Bokai Zhu, assistant professor in Pittsburgh’s department of medicine and the ageing institute.
Zhu said: “Our research is painting a picture where dysregulation of nuclear speckles is important for neuron degeneration in the context of many diseases.
“The concept of rejuvenating nuclear speckles to treat these diseases is completely novel, but I believe it’s the next frontier of neurodegenerative research.”
Using optical tweezers – laser tools for manipulating microscopic structures – the researchers found the drug lowered the surface tension of nuclear speckles, making them less round and easier to stretch and rupture.
This allowed them to spread out and make better contact with chromosomes, improving regulation of genes involved in protein control.
“This was the killer experiment,” said Zhu.
“Unlike most drugs, which target a specific receptor, pyrvinium pamoate acts by changing the surface tension of nuclear speckles.
This is a totally new idea. Because nuclear speckles act globally on chromosomes, the drug can potentially alter the expression of hundreds of genes — which may be why it is so effective.”
The researchers now aim to move towards clinical trials to test whether pyrvinium pamoate could effectively treat proteinopathies in humans.
