A jet lag ‘brain switch’ that controls the body clock may hold the key to a cure for Alzheimer’s disease, according to new research.
Experiments on fruit flies found turning it off killed rogue proteins that destroy neurons.
They had been genetically engineered to develop a devastating condition called Huntington’s disease, which has features of Parkinson’s disease, Alzheimer’s and motor neuron disease.
The US team induced ‘jet lag’ in the afflicted flies and unexpectedly found it protected their neurons.
The flies with jet lag were essentially moving four hours east every day. The traveling flies were more resilient than the flies who stayed on one schedule
Although fruit flies might seem completely different from humans, the neurons that govern flies’ sleep-wake cycles are strikingly similar.
They then identified and tested a gene called HOP (heatshock organizing protein) which is regulated by the body’s circadian rhythms.
It is also responsible for protein folding – a process linked to neurodegenerative illness. When knocked down, it stopped Huntington in its tracks.
The findings published in Cell Reports offer hope of a medicine to combat dementia, Parkinson’s, multiple sclerosis, Huntington’s and other disorders caused by faulty brain proteins.
Study leader Professor Ravi Allada, a circadian rhythms expert at Northwestern University, Evanston, Illinois, said: ‘It seems counter-intuitive, but we showed a little bit of stress is good.
‘We subtly manipulated the circadian clock, and that stress appears to be neuro-protective.’
Misfolded proteins, known as prions, shut down brain cells – eventually starving them to death.
This process can destroy movement or memory or even kill, depending on the disease.
It is thought to take place in many forms of neurodegeneration. Safely disrupting would treat a wide range of diseases.
Dr Allada and colleagues suspected HOP made an interesting target. They blocked it in the flies with the same protein that causes Huntington’s and, once more, were shocked by the results.
This restored their arrhythmic circadian clocks – as well as reducing the aggregation of diseased proteins and the number of neurons killed by them.
Dr Allada said: ‘We thought inhibiting this gene that helps your proteins fold properly would make things worse, but they got better. It again shows a little bit of stress is probably good.’
The researchers now plan to test the technique in a fruit fly model of Alzheimer’s.
Dr Allada believes targeting the HOP gene will be an early intervention for combating progression of various neuro-degenerative diseases.
Paradoxically, jet lag from travelling through different time zones could boost the brain – contrary to popular belief.
Patients with neurodegenerative diseases often experience profound disruptions in their circadian rhythms, or sleep-wake cycles.
They may sleep more than usual or lose the ability to stay asleep. This can lead to nighttime wandering, increased agitation, general stress and a decreased quality of life.
Dr Allada said: ‘We have long known that a disrupted clock is an early indicator of neurodegenerative disease.
‘In many cases, sleep disruption precedes any other symptom. But we didn’t know whether the circadian disruption is a cause or consequence of the disease.’
Fruit flies that have the mutant Huntington’s gene also demonstrate similar symptoms.
These include reduced lifespan, motor deficits, neurodegeneration, disrupted circadian rhythms and an accumulation of diseased proteins in the brain, which clump together and cause neurons to die.
Dr Allada said: ‘Normally, fruit flies wake up, get very active, then go to sleep and become inactive.
‘It’s a 24-hour pattern. In the Huntington model, there is no rhythm. The flies wake up and fall asleep all the time.’
His researchers altered the flies’ circadian rhythms two different ways either by changing the daily timing of light-dark cycles – causing them to live a 20 instead of 24 hour day – or through mutating a body clock gene.
Dr Allada said: ‘We essentially gave the flies jet lag for every day of their lives. It is like travelling four hours east every day.’
In both cases, the mutant Huntington disease proteins aggregated less and fewer neurons died. Dr Allada expected jet lag to inflict even more damage on the brain.
He said: ‘We had wondered if the clock played a role in the disease. It turned out that the clock was important – but in a manner that we did not predict.’
His team were so fascinated they took the study one step further by screening through dozens of clock-controlled genes.
They pinpointed HOP – suggesting all brain cell death from prion disease could be prevented.