tag:theconversation.com,2011:/fr/topics/brain-proteins-5394/articlesBrain proteins – The Conversation2022-05-27T03:07:52Ztag:theconversation.com,2011:article/1819542022-05-27T03:07:52Z2022-05-27T03:07:52ZOn your back? Side? Face-down? Mice show how we sleep may trigger or protect our brain from diseases like ALS<figure><img src="https://images.theconversation.com/files/462143/original/file-20220510-18-s2q22z.jpg?ixlib=rb-1.1.0&rect=35%2C35%2C5955%2C3952&q=45&auto=format&w=496&fit=clip" /><figcaption><span class="caption">
</span> <span class="attribution"><a class="source" href="https://images.unsplash.com/photo-1531353826977-0941b4779a1c?ixlib=rb-1.2.1&ixid=MnwxMjA3fDB8MHxwaG90by1wYWdlfHx8fGVufDB8fHx8&auto=format&fit=crop&w=3270&q=80">Unsplash/Lux Graves</a>, <a class="license" href="http://creativecommons.org/licenses/by/4.0/">CC BY</a></span></figcaption></figure><p>Amyotrophic lateral sclerosis (ALS), also known as Lou Gehrig’s disease, is the <a href="http://dx.doi.org/10.1136/jnnp.61.2.131">most common form</a> of motor neuron disease. People with ALS progressively lose the ability to initiate and control muscle movements, including the ability to speak, swallow and breathe. </p>
<p>There is no known cure. But recently, <a href="https://translationalneurodegeneration.biomedcentral.com/articles/10.1186/s40035-022-00291-4">we studied mice</a> and identified a new target in the fight against this devastating disease: the brain’s waste clearance system. </p>
<p><a href="https://www.nature.com/articles/s41593-018-0235-9">Neurodegenerative diseases</a> – including Parkinson’s disease, Alzheimer’s and multiple sclerosis – share many similarities, even though their clinical symptoms and disease progression may look very different. The incidence of these diseases increase with age. They are progressive and relentless, and result in gradual loss of brain tissue. We also see waste proteins accumulate in the brain. </p>
<p>Our new research looked at how the glymphatic system, which removes waste from the brain, could prevent ALS.</p>
<hr>
<p>
<em>
<strong>
Read more:
<a href="https://theconversation.com/als-is-only-50-genetic-identifying-dna-regions-affected-by-lifestyle-and-environmental-risk-factors-could-help-pinpoint-avenues-for-treatment-179169">ALS is only 50% genetic – identifying DNA regions affected by lifestyle and environmental risk factors could help pinpoint avenues for treatment</a>
</strong>
</em>
</p>
<hr>
<h2>Protein chains, folds and misfolds</h2>
<p>Inside our bodies, long protein chains fold to form functional shapes that allow them to perform <a href="https://medlineplus.gov/genetics/understanding/howgeneswork/protein/">specific tasks</a> like creating antibodies to fight off infection, supporting cells or transporting molecules. </p>
<p>Sometimes this process goes awry, resulting in “misfolded” proteins that clump together to form aggregates. Misfolded protein can grow and fragment, creating seeds that spread throughout the brain to form new clusters.</p>
<p>The accumulation of waste proteins begins early in the neurodegenerative disease process – well before the onset of symptoms and brain loss. As researchers, we wanted to see if eliminating or slowing the spread of these waste proteins and their seeds could halt or slow the progression of disease.</p>
<h2>Targeting waste removal</h2>
<p>The <a href="https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4636982/">glymphatic system</a> removes waste, including toxic proteins, from the brain. </p>
<p>This brain-wide network of fluid-filled spaces, known as <a href="https://fluidsbarrierscns.biomedcentral.com/articles/10.1186/s12987-015-0010-1">Virchow-Robin spaces</a>, is mostly switched off while we’re awake. But it kicks into gear during sleep to distribute compounds essential to brain function and to get rid of toxic waste. </p>
<p>This may explain why <a href="https://theconversation.com/animals-sleep-but-little-is-known-about-how-sharks-do-it-180219">all creatures</a>, great and small (<a href="https://qbi.uq.edu.au/article/2013/08/flies-sleep-just-us">even flies</a>), need sleep to survive. (Interestingly, whales and dolphins alternate their sleep between brain hemispheres, keeping the other hemisphere awake to watch for predators and alerting them to breathe!)</p>
<figure class="align-center zoomable">
<a href="https://images.theconversation.com/files/462145/original/file-20220510-17-ip9qf6.jpg?ixlib=rb-1.1.0&q=45&auto=format&w=1000&fit=clip"><img alt="pair of dolphins underwater" src="https://images.theconversation.com/files/462145/original/file-20220510-17-ip9qf6.jpg?ixlib=rb-1.1.0&q=45&auto=format&w=754&fit=clip" srcset="https://images.theconversation.com/files/462145/original/file-20220510-17-ip9qf6.jpg?ixlib=rb-1.1.0&q=45&auto=format&w=600&h=399&fit=crop&dpr=1 600w, https://images.theconversation.com/files/462145/original/file-20220510-17-ip9qf6.jpg?ixlib=rb-1.1.0&q=30&auto=format&w=600&h=399&fit=crop&dpr=2 1200w, https://images.theconversation.com/files/462145/original/file-20220510-17-ip9qf6.jpg?ixlib=rb-1.1.0&q=15&auto=format&w=600&h=399&fit=crop&dpr=3 1800w, https://images.theconversation.com/files/462145/original/file-20220510-17-ip9qf6.jpg?ixlib=rb-1.1.0&q=45&auto=format&w=754&h=501&fit=crop&dpr=1 754w, https://images.theconversation.com/files/462145/original/file-20220510-17-ip9qf6.jpg?ixlib=rb-1.1.0&q=30&auto=format&w=754&h=501&fit=crop&dpr=2 1508w, https://images.theconversation.com/files/462145/original/file-20220510-17-ip9qf6.jpg?ixlib=rb-1.1.0&q=15&auto=format&w=754&h=501&fit=crop&dpr=3 2262w" sizes="(min-width: 1466px) 754px, (max-width: 599px) 100vw, (min-width: 600px) 600px, 237px"></a>
<figcaption>
<span class="caption">Unlike us, dolphins sleep with one side of their brain at a time.</span>
<span class="attribution"><a class="source" href="https://images.unsplash.com/photo-1562742686-0b38a29473ab?ixlib=rb-1.2.1&ixid=MnwxMjA3fDB8MHxwaG90by1wYWdlfHx8fGVufDB8fHx8&auto=format&fit=crop&w=3273&q=80">Unsplash/NOAA</a>, <a class="license" href="http://creativecommons.org/licenses/by/4.0/">CC BY</a></span>
</figcaption>
</figure>
<p>As we age, sleep quality <a href="https://doi.org/10.1111/j.1532-5415.2008.01755.x">declines</a> and the risk of neurodegenerative disease, including ALS, increases. </p>
<p>Sleep disturbances are also a common symptom of ALS and research has shown a single night without sleep can result in <a href="https://www.pnas.org/doi/10.1073/pnas.1721694115">increased accumulation</a> of toxic waste protein in the brain. As such, we thought glymphatic function might be impaired in ALS. </p>
<hr>
<p>
<em>
<strong>
Read more:
<a href="https://theconversation.com/longer-naps-in-the-day-may-be-an-early-sign-of-dementia-in-older-adults-179365">Longer naps in the day may be an early sign of dementia in older adults</a>
</strong>
</em>
</p>
<hr>
<h2>Ageing mice</h2>
<p>To investigate this, we looked to mice. The animals were genetically modified to express human TDP-43 – the protein implicated in ALS. By feeding these mice food containing an antibiotic (doxycycline), we were able to turn the TDP-43 protein expression off and they aged normally. But when the mice are switched to normal food, TDP-43 expression is turned on and misfolded proteins begin to accumulate. </p>
<p>Over time, the mice display the classical signs of ALS including progressive muscle impairments and brain atrophy. </p>
<p>Using magnetic resonance imaging (MRI) to see brain structure, we investigated glymphatic function in these mice just three weeks after turning on TDP-43 expression.</p>
<p>As we watched the glymphatic system go to work, we saw the TDP-43 mice had worse glymphatic clearance than the control mice that had not been genetically modified. Importantly, these differences were seen very early in the disease process. </p>
<p>Our study provides the first evidence the glymphatic system might be a potential therapeutic target in the treatment of ALS.</p>
<p><div data-react-class="Tweet" data-react-props="{"tweetId":"1508474747537039367"}"></div></p>
<h2>How can we improve glymphatic function?</h2>
<p>Not all sleep is equal. Sleep includes both rapid eye movement (REM) and non-REM sleep. This latter stage includes slow wave sleep – <a href="https://www.ncbi.nlm.nih.gov/pmc/articles/PMC7309589/">when the glymphatic system is most active</a>. Sleep therapies that enhance this phase may prove to be particularly beneficial for preventing diseases like ALS. </p>
<p>Sleep position is also thought to affect glymphatic clearance. </p>
<p>Research conducted in rodents has <a href="https://pubmed.ncbi.nlm.nih.gov/26245965/">demonstrated</a> glymphatic clearance is most efficient in the lateral (or side-sleeping) position, compared to either supine (on the back) or prone (front-lying) positions. The reasons for this are not yet fully understood but possibly relates to the effects of gravity, compression and stretching of tissue.</p>
<hr>
<p>
<em>
<strong>
Read more:
<a href="https://theconversation.com/sleeping-on-it-helps-you-better-manage-your-emotions-and-mental-health-heres-why-179156">‘Sleeping on it’ helps you better manage your emotions and mental health – here’s why</a>
</strong>
</em>
</p>
<hr>
<p>Lifestyle choices may be helpful in improving glymphatic function too. <a href="https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6747747/">Omega-3</a>, found in marine-based fish, has long been considered to be beneficial to health and reduced risk of neurodegenerative diseases. New research shows these benefits may be partly due to the positive effect of <a href="https://pubmed.ncbi.nlm.nih.gov/27789520/">Omega-3 on glymphatic function</a>.</p>
<p>Moderate consumption of alcohol has been shown to improve waste clearance. In mouse studies, both short and long-term exposure to <a href="https://pubmed.ncbi.nlm.nih.gov/29396480/">small amounts of alcohol were shown to boost glymphatic function</a> while high doses had the opposite effect. </p>
<p><a href="https://pubmed.ncbi.nlm.nih.gov/28579942/">Exercise</a> has also been shown to be beneficial. </p>
<p>All these studies show small lifestyle changes can improve brain waste clearance to minimise the risk of neurodegenerative disease. Next, research needs to focus on therapies directly targeting the glymphatic system to help those already suffering from these debilitating diseases.</p><img src="https://counter.theconversation.com/content/181954/count.gif" alt="The Conversation" width="1" height="1" />
<p class="fine-print"><em><span>David Wright receives funding from the NHMRC and FightMND. He has previously received funding from the Bethlehem Griffiths Research Foundation to investigate glymphatic function in ALS.</span></em></p>Our new research with mice visualised how differently aged brains pump out toxic protein waste during sleep.David Wright, Associate Professor of Medical Imaging, Monash UniversityLicensed as Creative Commons – attribution, no derivatives.tag:theconversation.com,2011:article/152762013-06-25T04:33:38Z2013-06-25T04:33:38ZExercise and prosper: lessons about the brain from the bomb<figure><img src="https://images.theconversation.com/files/26105/original/mwdmns2b-1372124038.jpg?ixlib=rb-1.1.0&q=45&auto=format&w=496&fit=clip" /><figcaption><span class="caption">Measuring how much of a carbon isotope linked to the atomic bomb is in DNA indicates when the cells were born.</span> <span class="attribution"><span class="source">Sin Amigos</span></span></figcaption></figure><p>Until a few years ago, it was assumed that humans were born with the maximum number of neurons that we were ever going to have. There was no chance of self-replenishment as we got older, or if we suffered some sort of neurological disease or trauma. But our understanding of the brain is changing all that and there’s good news.</p>
<p>While we thought that the human brain was more or less static, studies in <a href="http://www.ncbi.nlm.nih.gov/pubmed/21460835">mice and rats</a> had shown that they make new neurons throughout life. Many of these neurons are made in a region of the brain called the hippocampus, which plays an essential role in learning and forming new memories. </p>
<p>Remarkably, these newborn neurons are able to form connections (synapses) with pre-existing cells. The strength and effectiveness of these new, immature synapses is especially dependent on the level of electrical activity within the newly-made neuronal networks.</p>
<p>This means that the new circuits are highly adaptable, changing in response to life’s experiences. These changes are believed to be especially important when laying down new memories in adult brains.</p>
<p>Until now, these insights into adult learning and memory were restricted to studies in rodents, but a <a href="http://www.ncbi.nlm.nih.gov/pubmed/23746839">landmark paper</a> published earlier this month in the journal Cell finally provides proof that new neurons are also made throughout life in a critical part of the human hippocampus.</p>
<p>The research changes the way we think about our brains and how they are altered. </p>
<h2>The research</h2>
<p>The authors (Kirsty Spalding and colleagues) made the breakthrough by inventing an extraordinarily complex technique that measures the amount of carbon isotope 14 (C14) in the DNA of human cells obtained post mortem. </p>
<p>C14 levels in the atmosphere peaked during the period of above-ground atomic bomb tests in the 1950s and early 1960s, and have declined ever since. </p>
<p>When cells divide, they incorporate carbon into the newly formed DNA, so measurement of how much C14 is in DNA gives an indication of when the cells were born.</p>
<p>The measurements reveal surprisingly high levels of neurogenesis in the hippocampus and show that it continues into old age. The new cells are born in a part of the hippocampus called the dentate gyrus, a region essential for forming and consolidating memories. </p>
<p>Using complex modelling, the researchers calculated that there’s a sub-population of hippocampal neurons (about a third of them, probably comprising most of the dentate gyrus) that is continually renewed. This proportion of “exchangeable” neurons is much higher in humans than in rodents. </p>
<p>The generation of new cells is similar in males and females, and declines slightly with age, although the decline is nowhere near as great as documented in mice and rats. </p>
<p>Interestingly, neurons in the non-renewing population are gradually lost throughout life, and adult-born cells in the renewable sub-population appear not to survive for more than about 10 years. So, overall, we do end up with fewer hippocampal neurons at 80 than at 20.</p>
<h2>What it means for you</h2>
<p>In <a href="http://www.sciencemag.org/content/340/6137/1180.summary">a commentary on the paper</a> published in Science, Gerd Kempermann suggests that renewal of neurons in the dentate gyrus allows us to “cope with change and novelty” and might even “prominently contribute to the individualization of the brain and thus the shaping of personality”. </p>
<p>The authors of the Cell paper themselves raise the tantalising possibility that reduced neurogenesis in the human brain may be a factor in psychiatric disease. </p>
<p>Reduced neurogenesis has been <a href="http://www.ncbi.nlm.nih.gov/pubmed/23042885">suggested to occur</a> in depression and other mood disorders, and perhaps also in <a href="http://www.ncbi.nlm.nih.gov/pubmed/22410582">Alzheimer’s disease</a>. The possibility of manipulating neuron formation as a type of therapy for neurological disease has more substance now. </p>
<p>The finding also provides clues as to how we can best nurture our brain as we get older. It’s well established that <a href="http://www.ncbi.nlm.nih.gov/pubmed/21699941">exercise increases</a> the number of new neurons born in mouse hippocampus. One important factor underlying this effect is a protein, called brain-derived neurotrophic factor (BDNF), levels of which are increased in physically active animals. </p>
<p>There’s an <a href="http://www.ncbi.nlm.nih.gov/pubmed/21531985">age-related decline</a> in BDNF concentrations but having a bigger hippocampus is linked to higher levels of the protein. And the hippocampus is larger in people who exercise, so physical activity may increase the factors that aid neurogenesis in our brains. </p>
<p>All the more reason then to walk to the corner store, ride that bicycle, or go to the pool for a swim. You might just be doing your brain some good. And watch this space for more practical lessons from cutting-edge brain science.</p><img src="https://counter.theconversation.com/content/15276/count.gif" alt="The Conversation" width="1" height="1" />
<p class="fine-print"><em><span>Alan Harvey receives funding from NHMRC and ARC, and WA Neurotrauma Research Program</span></em></p>Until a few years ago, it was assumed that humans were born with the maximum number of neurons that we were ever going to have. There was no chance of self-replenishment as we got older, or if we suffered…Alan Harvey, Winthrop Professor of Anatomy, Physiology and Human Biology, The University of Western AustraliaLicensed as Creative Commons – attribution, no derivatives.