Lewy body dementia: Drug halts progression in mice

• A drug candidate called SAK3 prevented further loss of motor and cognitive function in a mouse model of Lewy body dementia, which affects some people with Parkinson’s disease.
• The drug appears to work by activating a mechanism for disposing of clumps of misfolded proteins.
• The new study adds to previous research that suggests SAK3 could treat a range of brain disorders that involve protein misfolding, including Alzheimer’s disease and Huntington’s disease.
• The scientists hope to start clinical trials of the drug within a year.

Lewy body dementia is the third most common type of dementia after Alzheimer’s disease and vascular dementia. The condition accounts for 5–10% of all cases.

People with Lewy body dementia experience the difficulties with movement that characterize Parkinson’s disease, as well as depression, anxiety, and a progressive loss of thinking and reasoning skills.

Towards the end of his life, the actor and comedian Robin Williams had Lewy body dementia, though doctors only diagnosed it after his death.

The defining features of the disease in the brain are the loss of neurons, which transmit information, and the presence of Lewy bodies, which are clumps of a misfolded protein called alpha-synuclein, only detectable in postmortem studies.

The protein clumps may be responsible for the death of dopamine neurons, leading to problems with movement, learning, and memory.

Misfolded molecules of another protein called beta-amyloid can aggregate to form the toxic plaques that widely feature in Alzheimer’s disease.

Similarly, misfolded proteins may be responsible for several other neurodegenerative disorders, including Huntington’s disease and “tauopathies,” which are characterized by tangles of fibrils made from a protein called tau.

Protein mincing machine

Typically, a piece of cellular machinery called the proteasome identifies and disposes of these misfolded proteins.

“The proteasome is the cell’s mincing machine which grinds up bad proteins,” explained Professor David Dexter, Associate Director of Research at the charity Parkinson’s UK.

“It stops working properly in many conditions, including Parkinson’s, and this leads to the buildup of unwanted proteins which damage brain cells,” he told Medical News Today.

So a drug that boosts proteasome activity could, in theory, stop these diseases in their tracks.

Scientists at Tohoku University in Sendai, Japan, believe they may have found such a drug, which they call SAK3.

They have tested the drug in a series of experiments involving mouse models of neurodegenerative disease, the latest of which appears in the International Journal of Molecular Sciences.

“We discovered the novel, disease-modifying therapeutic candidate SAK3, which, in our studies, rescued neurons in most protein-misfolding, neurodegenerative diseases,” says senior author Kohji Fukunaga, Professor Emeritus in the University’s Graduate School of Pharmaceutical Sciences.

Influx of calcium ions

Previous research by Prof. Fukunaga and his colleagues showed that SAK3 activates a molecular channel in the membrane of neurons that allows calcium ions to flow into the cells.

The resulting influx of calcium ions appears to have two effects. It not only increases the release of dopamine and another neurotransmitter called acetylcholine — which deplete in Alzheimer’s and Lewy body dementia — but also fires up the proteasome.

The researchers’ previous work in a mouse model of Alzheimer’s found that this inhibited the formation of beta amyloid plaques.

In the new study, the researchers investigated whether SAK3 also promotes the destruction of misfolded alpha-synuclein in a mouse model of Lewy body dementia.

The researchers gave some mice daily oral doses of SAK3 for 3 months. Results showed significantly less of the misfolded protein in a part of these animals’ brains called the substantia nigra than in the control animals.

This region contains dopamine-producing neurons and is a focus of damage in Parkinson’s disease.

As a result of the improved disposal of misfolded alpha-synuclein, SAK3 appeared to prevent the death of dopamine neurons.

Crucially, behavioral tests showed that the drug also reduced declines in motor performance and memory.

“Even after the onset of cognitive impairment, SAK3 administration significantly prevented the progression of neurodegenerative behaviors in both motor dysfunction and cognition,” says Prof. Fukunaga.

Clinical trials on the horizon

“SAK3 administration promotes the destruction of misfolded proteins, meaning the therapeutic has the potential to solve the problems of diverse protein misfolding diseases, such as Parkinson’s disease, Lewy body dementia, and Huntington disease, in addition to Alzheimer’s disease,” he adds.

Prof. Dexter cautioned that there remains much more work to do.

“While these findings are encouraging, this research is still at an early stage,” he said.

“The next crucial step will be to take this potential new drug forwards to test in people in clinical trials. That’s when we’ll know whether it truly could be a game-changing treatment for people with degenerative brain conditions.”

Prof. Fukunaga confirmed in an email to Medical News Today that his team is seeking a partner to carry out clinical trials of SAK3 in the United States. They hope to start trials within a year.

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