Learning and remembering movement


From the moment we are born, and even before that, we interact with the world through movement. We move our lips to smile or to talk. We extend our hand to touch. We move our eyes to see. We wiggle, we walk, we gesture, we dance. How does our brain remember this wide range of motions? How does it learn new ones? How does it make the calculations necessary for us to grab a glass of water, without dropping it, squashing it, or missing it?

Technion Professor Jackie Schiller from the Ruth and Bruce Rappaport Faculty of Medicine and her team examined the brain at a single-neuron level to shed light on this mystery. They found that computation happens not just in the interaction between neurons (nerve cells ), but within each individual neuron. Each of these cells, it turns out, is not a simple switch, but a complicated calculating machine. This discovery, published recently in the Science magazine, promises changes not only to our understanding of how the brain works, but better understanding of conditions ranging from Parkinson’s disease to autism. And if that weren’t enough, these same findings are expected to advance machine learning, offering inspiration for new architectures.

Movement is controlled by the primary motor cortex of the brain. In this area, researchers are able to pinpoint exactly which neuron(s) fire at any given moment to produce the movement we see. Prof. Schiller’s team was the first to get even closer, examining the activity not of the whole neuron as a single unit, but of its parts.

Every neuron has branched extensions called dendrites. These dendrites are in close contact with the terminals (called axons) of other nerve cells, allowing the communication between them. A signal travels from the dendrites to the cell’s body, and then transferred onwards through the axon. The number and structure of dendrites varies greatly between nerve cells, like the crown of one tree differs from the crown of another.

The particular neurons Prof. Schiller’s team focused on were the largest pyramidal neurons of the cortex. These cells, known to be heavily involved in movement, have a large dendritic tree, with many branches, sub-branches, and sub-sub-branches. What the team discovered is that these branches do not merely pass information onwards. Each sub-sub-branch performs a calculation on the information it receives and passes the result to the bigger sub-branch. The sub-branch than performs a calculation on the information received from all its subsidiaries and passes that on. Moreover, multiple dendritic branchlets can interact with one another to amplify their combined computational product. The result is a complex calculation performed within each individual neuron. For the first time, Prof. Schiller’s team showed that the neuron is compartmentalised, and that its branches perform calculations independently.

“We used to think of each neuron as a sort of whistle, which either toots, or doesn’t,” Prof. Schiller explains. “Instead, we are looking at a piano. Its keys can be struck simultaneously, or in sequence, producing an infinity of different tunes.” This complex symphony playing in our brains is what enables us to learn and perform an infinity of different, complex and precise movements.

Multiple neurodegenerative and neurodevelopmental disorders are likely to be linked to alterations in the neuron’s ability to process data. In Parkinson’s disease, it has been observed that the dendritic tree undergoes anatomical and physiological changes. In light of the new discoveries by the Technion team, we understand that as a result of these changes, the neuron’s ability to perform parallel computation is reduced. In autism, it looks possible that the excitability of the dendritic branches is altered, resulting in the numerous effects associated with the condition. The novel understanding of how neurons work opens new research pathways with regards to these and other disorders, with the hope of their alleviation.

These same findings can also serve as an inspiration for the machine learning community. Deep neural networks, as their name suggests, attempt to create software that learns and functions somewhat similarly to a human brain. Although their advances constantly make the news, these networks are primitive compared to a living brain. A better understanding of how our brain actually works can help in designing more complex neural networks, enabling them to perform more complex tasks.

Disease-modifying antirheumatic drugs do not seem to protect people with rheumatoid arthritis against Parkinson’s disease


The autoimmune disorder rheumatoid arthritis has been associated with a lower risk of Parkinson’s disease (PD) in previous studies, with antirheumatic drugs as one possible explanation. However, most of the disease-modifying antirheumatic drugs (DMARDs) were not associated with the risk of PD in individuals with rheumatoid arthritis, a new register-based study from the University of Eastern Finland shows. An exception was the use of chloroquine or hydroxychloroquine which associated with a lower risk of PD. The findings were published online on January 21, 2022, in Neurology®, the medical journal of the American Academy of Neurology.

Risk factors for PD are still unclear. Rheumatoid arthritis has been linked to PD with conflicting findings, and both risk lowering and increasing findings have been reported. The medications used to treat rheumatoid arthritis could be one possible explanation for the potential lower risk of PD in individuals with rheumatoid arthritis but there are only few previous studies.

According to the newly published study, previous use of methotrexate, sulfasalazine, gold preparations or immunosuppressants at least three years before the PD diagnosis was not associated with the risk of PD in individuals with rheumatoid arthritis. However, users of chloroquine or hydroxychloroquine had a 26% lower relative risk of PD. Different comorbidities, such as cardiovascular diseases and diabetes, along with age, sex, and duration of rheumatoid arthritis, were controlled for in the study.

Chloroquine and the more commonly used hydroxychloroquine have various effects on the immune system. These medicines have been found to have antiparkinson potential in animal models of PD. According to researchers, the possible protective association of chloroquine and hydroxychloroquine should be further investigated.

This study was conducted as part of the FINPARK study, which covers 22,189 community-dwelling Finns with PD and a matched comparison cohort. The study was limited to persons who had been diagnosed with rheumatoid arthritis at least three years before PD.

Discovery raises possibility of new medication for Alzheimer’s, Parkinson’s and MS

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Researchers from Oregon Health & Science University have for the first time demonstrated it’s possible to use a synthetic thyroid hormone to regulate a gene implicated in neurodegenerative diseases like Alzheimer’s, Parkinson’s and multiple sclerosis.

The findings from tests in cells and mice, published today in the journal Cell Chemical Biology, raise the possibility of development of new medication to treat debilitating diseases.

“This is the first example reported that shows it’s possible to increase the expression of the TREM2 gene in a way that will lead to healing in certain diseases,” said senior author Tom Scanlan, Ph.D., professor of physiology and pharmacology in the OHSU School of Medicine. “This will generate a lot of excitement.”

The paper’s first author is Skylar J. Ferrara, Ph.D., a postdoctoral fellow in the OHSU School of Medicine’s chemical physiology and biochemistry department. 

The discovery builds on a 2013 publication linking genetic variants of TREM2 to risk of Alzheimer’s disease.

The new research from OHSU builds on that work by showing that it’s possible to turn on TREM2 expression and the TREM2 pathway using a compound originally developed more than two decades ago to lower cholesterol.

Researchers administered an analog of the compound that penetrates into the central nervous system of mice. They discovered they were able to increase the expression of TREM2 and reduce damage to myelin. Myelin is the insulation-like protective sheath covering nerve fibers that’s damaged in disorders like multiple sclerosis. 

The pathway activated by the TREM2 gene is also implicated in neurodegenerative diseases, including Alzheimer’s and Parkinson’s.

“TREM2 is a receptor,” Scanlan said. “It senses damaged cellular debris from disease and responds in a healing, productive way. The thought is, if you can simply turn up its expression, then that’s going to lead to a therapeutic effect in most neurodegenerative diseases.” 

Joseph Quinn, M.D., professor of neurology in the OHSU School of Medicine, who treats patients with Parkinson’s and Alzheimer’s, said the findings are promising. Quinn wasn’t involved in the research.

“TREM2 is a viable ‘target’ for treatment in Alzheimer’s disease, based on genetics and other studies,” Quinn said. “This new report has important implications for testing a new therapeutic approach for Alzheimer’s, including raising the potential for developing a new medication to regulate TREM2.”

The synthetic thyroid hormone compound, known as sobetirome and similar analogs, is already licensed by an OHSU spinoff company to conduct clinical trials for central nervous system diseases, including multiple sclerosis. In contrast to other basic science discoveries in mice, Scanlan said this latest discovery connects this class of compounds to Alzheimer’s, Parkinson’s and other neurodegenerative diseases, advancing the science that much closer to clinical trials in people with debilitating disease.  

“The possibility of doing clinical trials is not millions of miles away,” Scanlan said. “It would be an achievable thing.”

Parkinson’s, cancer, type 2 diabetes share a key element that drives disease

Parkin protein (green signal) is in a different part of the cell than the mitochondria (red signal) at time 0 (left image) but then co-localizes with the mitochondria after 60 minutes (right image). CREDIT Salk Institute

When cells are stressed, chemical alarms go off, setting in motion a flurry of activity that protects the cell’s most important players. During the rush, a protein called Parkin hurries to protect the mitochondria, the power stations that generate energy for the cell. Now Salk researchers have discovered a direct link between a master sensor of cell stress and Parkin itself. The same pathway is also tied to type 2 diabetes and cancer, which could open a new avenue for treating all three diseases.

“Our findings represent the earliest step in Parkin’s alarm response that anyone’s ever found by a long shot. All the other known biochemical events happen at one hour; we’ve now found something that happens within five minutes,” says Professor Reuben Shaw, director of the NCI-designated Salk Cancer Center and senior author of the new work, detailed in Science Advances on April 7, 2021. “Decoding this major step in the way cells dispose of defective mitochondria has implications for a number of diseases.”

Parkin’s job is to clear away mitochondria that have been damaged by cellular stress so that new ones can take their place, a process called mitophagy. However, Parkin is mutated in familial Parkinson’s disease, making the protein unable to clear away damaged mitochondria. While scientists have known for some time that Parkin somehow senses mitochondrial stress and initiates the process of mitophagy, no one understood exactly how Parkin was first sensing problems with the mitochondria–Parkin somehow knew to migrate to the mitochondria after mitochondrial damage, but there was no known signal to Parkin until after it arrived there.

Shaw’s lab, which is well known for their work in the fields of metabolism and cancer, spent years intensely researching how the cell regulates a more general process of cellular cleaning and recycling called autophagy. About ten years ago, they discovered that an enzyme called AMPK, which is highly sensitive to cellular stress of many kinds, including mitochondrial damage, controls autophagy by activating an enzyme called ULK1.

Following that discovery, Shaw and graduate student Portia Lombardo began searching for autophagy-related proteins directly activated by ULK1. They screened about 50 different proteins, expecting about 10 percent to fit. They were shocked when Parkin topped the list. Biochemical pathways are usually very convoluted, involving up to 50 participants, each activating the next. Finding that a process as important as mitophagy is initiated by only three participants–first AMPK, then ULK1, then Parkin–was so surprising that Shaw could scarcely believe it.

To confirm the findings were correct, the team used mass spectrometry to reveal precisely where ULK1 was attaching a phosphate group to Parkin. They found that it landed in a new region other researchers had recently found to be critical for Parkin activation but hadn’t known why. A postdoctoral fellow in Shaw’s lab, Chien-Min Hung, then did precise biochemical studies to prove each aspect of the timeline and delineated which proteins were doing what, and where. Shaw’s research now begins to explain this key first step in Parkin activation, which Shaw hypothesizes may serve as a “heads-up” signal from AMPK down the chain of command through ULK1 to Parkin to go check out the mitochondria after a first wave of incoming damage, and, if necessary, trigger destruction of those mitochondria that are too gravely damaged to regain function.

The findings have wide-ranging implications. AMPK, the central sensor of the cell’s metabolism, is itself activated by a tumor suppressor protein called LKB1 that is involved in a number of cancers, as established by Shaw in prior work, and it is activated by a type 2 diabetes drug called metformin. Meanwhile, numerous studies show that diabetes patients taking metformin exhibit lower risks of both cancer and aging comorbidities. Indeed, metformin is currently being pursued as one of the first ever “anti-aging” therapeutics in clinical trials.

“The big takeaway for me is that metabolism and changes in the health of your mitochondria are critical in cancer, they’re critical in diabetes, and they’re critical in neurodegenerative diseases,” says Shaw, who holds the William R. Brody Chair. “Our finding says that a diabetes drug that activates AMPK, which we previously showed can suppress cancer, may also help restore function in patients with neurodegenerative disease. That’s because the general mechanisms that underpin the health of the cells in our bodies are way more integrated than anyone could have ever imagined.”

Convincing evidence that type 2 diabetes is associated with increased risk of Parkinson’s

Should autistic people be eligible for disabled parking spaces?


Research from Queen Mary University of London has concluded that type 2 diabetes is associated with an increased risk of Parkinson’s disease and that type 2 diabetes may contribute to faster disease progression in patients with Parkinson’s

Research from Queen Mary University of London has concluded that there is convincing evidence that type 2 diabetes is associated with an increased risk of Parkinson’s disease. The same study found that there was also evidence that type 2 diabetes may contribute to faster disease progression in patients who already have Parkinson’s.

Treating people with drugs already available for type 2 diabetes may reduce the risk and slow the progression of Parkinson’s. Screening for and early treatment of type 2 diabetes in patients with Parkinson’s may be advisable.

Previous systematic reviews and meta-analyses have produced conflicting results around the link between diabetes and the risk of Parkinson’s disease. This new study, published in the Movement Disorders Journal, used meta-analysis of observational data and meta-analysis of genetic data to evaluate the effect of type 2 diabetes on risk and progression of Parkinson’s disease.

Corresponding author Dr Alastair Noyce from Queen Mary University of London said: “This research brings together the results from many other studies to provide convincing evidence that type 2 diabetes likely affects not only Parkinson’s risk, but also Parkinson’s progression. There are many treatment strategies for type 2 diabetes, including prevention strategies, which may be re-purposed for the treatment of Parkinson’s.”