Discovery of a new mechanism of action of a protein that is toxic in Parkinson’s disease

A team coordinated by Antoine Triller, Inserm Research Director, Director of the Institute of Biology at the École Normale Supérieure, and Ronald Melki, CNRS Research Director (Paris-Saclay Institute of Neuroscience), has just identified the target of an alpha-synuclein protein, which is pathogenic in Parkinson’s disease. This target is an ATP-dependent sodium/potassium pump. It may potentially be used in the development of symptomatic treatments for Parkinson’s disease. Details of this work are published in the 31 August 2015 issue of The EMBO Journal.Triller

Alpha-synuclein forms fibrils (grey) that adhere (red) to the membrane of neurons (green). On the right side of the figure: the fibrils (red), on aggregating, disrupt the function of the pump (green) that maintains the sodium (Na+) gradient. This depolarises the neuron and increases the entry of calcium (Ca2+), which is toxic to the neuron. © Inserm/Antoine Triller

Alpha-synuclein is one of the pathogenic proteins (along with the tau and beta-amyloid proteins for Alzheimer’s disease, or prion protein for Kreutzfeldt-Jacob disease) that spread from cell to cell, and are associated with the physiopathological changes observed in neurodegenerative diseases.

Antoine Triller and his colleagues have shown that this protein aggregates on the neuronal membrane, and interacts with a protein on the surface of the neuron, the a3 subunit of the (Na+)/potassium (K+) ATPase pump. This pump controls the flow of sodium and potassium ions to and from the neurons, and hence the electrical activity of these neurons.

In humans, mutations in this pump are responsible for motor symptoms of early onset Parkinson’s disease, and alternating hemiplegia of childhood (AHC). The researchers have just demonstrated that alpha-synuclein, which diffuses between the cells, interacts with the Na+/K+ ATPase pump in the membrane. The pump, when bound to alpha-synuclein, is less well able to perform its pumping activity. Neuronal excitability is disrupted. Over time, the signals are no longer transmitted normally between neurons, and the symptoms of Parkinson’s disease or AHC appear.

This discovery was made possible through a combination of molecular biology and super-resolution microscopy techniques making it possible to follow individual molecules. In 2014, this latter approach was rewarded by the conferring of the Nobel Prize in Chemistry on Eric Betzig, Stephan W. Hell and William E. Moerner.

“This is a new mechanism that makes it possible to explain at cellular level the neuronal malfunctions in Parkinson’s disease,” explains Antoine Triller, Inserm Research Director. “This work sheds light on the fundamental and initial processes of the disease, and enables exploration of new therapeutic strategies to control its progression and symptoms,” he adds.

Observing the brain of moving animals

Such is the brain’s complexity that it is a particularly difficult organ to examine despite technological progress in this area. While electroencephalograms (EEG) and optical techniques can be used to record neurone activity in mobile animals, it is only possible to examine certain areas of the brain due to the size of the electrodes and light diffraction. Alternatively, functional ultrasound imaging (fUS) and magnetic resonance imaging (MRI) can be used to record variations in blood flow in the brain. Since active neurones need to be well-supplied with blood, blood flow in a given area reflects neurone activity in this area. However, these techniques require subjects to be completely immobile.Imagerie électro-encéphalographique

Electroencephalographic image. © Inserm/CRICM – Plateau MEG/EEG – Inserm U975

Two teams led by Ivan Cohen from Inserm Unit 1130 “Neuroscience Paris Seine” and Mickaël Tanter from Inserm Unit 979 “Wave physics for medicine” at the Langevin Institute (ESPCI/CNRS) have improved the fUS method to make it portable and usable with conscious and mobile rats at the same time as an EEG.

In order to demonstrate the benefits of this new method for pathological applications, the researchers looked at cerebral mechanisms in rats that reproduce epileptic seizures.

Thanks to this cutting-edge technology, we have precisely observed changes in blood flow which are precursors of epileptic seizure onset“, explains Inserm Research Fellow Ivan Cohen.

A study of cerebral mechanisms of mobile animals offers multiple opportunities for understanding behaviour and neurological conditions by mapping the regions of the brain associated with them. In particular, this technology will allow us to combine neurological and vascular data that play a key role in conditions such as dementia, strokes, epilepsy and Alzheimer’s disease.

Using Google Trends for suicide prevention?

“Google” is currently the most widely used search engine in the world. Google Trends is a tool that performs a statistical analysis of words entered in the search engine. During the influenza H1N1 epidemic in 2009, a strong spike in searches for the word “influenza” was observed in regions where the epidemic had begun. Thus Google Trends might be used to follow not only the spread of infectious epidemics, but that of other phenomena as well, such as suicide epidemics. This hypothesis led psychiatrist and researcher Guillaume Fond (Inserm Unit 955, Mondor Institute of Biomedical Research, IMRB, Créteil) and his team to study in greater detail the relationship between the number of Google searches for terms such as suicide, depression and bipolar disorder and the risk of a suicide “epidemic.” This work is published in the journal Psychiatry Research.

A suicide epidemic is a spike in the rate of suicide in a population at a particular time. This phenomenon has also been called the “Werther effect,” a reference to the increase in suicide that followed the publication of Goethe’s book The Sorrows of Young Werther in 1774.

The study conducted by Guillaume Fond and his collaborators was aimed at determining how Google Trends could help to monitor trends in searching for key words or key expressions such as “suicide,” or “how to commit suicide,” as well as “depression” and “bipolar disorder,” since bipolar mood disorder is strongly associated with suicide risk. 

“Detection of an increased search for the word “suicide” might make it possible to establish targeted prevention policies,” explain the researchers.

The work published this month shows several spikes from 2005 to 2015 in searches related to the word “suicide.” This research was not associated with searches for the words “depression or “bipolar.” These spikes in searches were sometimes associated with news stories that appeared on the Internet containing “suicide” as a key word. Other spikes were not associated with any events to be found on the Web. This does not exclude the possibility that reports or broadcasts disseminated through traditional channels (television, radio, hard copy print media) had an influence, but this was not taken into consideration for the purposes of this study.

These results confirmed the very strong influence of media on the search rates for key words associated with suicide and depression. Thus, searches for the word “bipolar” have progressively increased in France during the last decade. A spike was seen in this search in France as well as worldwide in 2011, when it was revealed that the actress Catherine Zeta-Jones has bipolar disorder.

The authors propose that the effect of Internet media influence on searches for psychiatric terms be called the “Zeta-Jones effect,” by analogy with the Werther effect.

To conclude, Google Trends is a tool that may provide some useful information for assessing the impact of media communication on mental illnesses, but the tool is not yet accurate enough to enable an effective suicide prevention policy.

Perspectives: a tool enabling a detailed analysis of some key words, such as “suicide,” or “how to commit suicide” on a weekly or even daily basis, with detailed geographic distribution, would make it possible to target suicide prevention policies appropriately and effectively. Through the same Google process that directs Internet users according to their interests as ascertained from their key words, it is conceivable that users could be directed to a free-phone number or crisis centre. This system could be particularly effective for adolescents.

“This process would be limited by individual freedom and respect for privacy, issues that are being strongly debated at the moment,” concludes Guillaume Fond.Symbolbild Zahlen Ziffern

Glucose to help blindness

The loss of cones, those photoreceptors located in the retina, is the major cause of disability for people with inherited retinal degeneration. Preventing their loss would prevent more than a million people worldwide from becoming blind.

Retinitis pigmentosa, a type of inherited retinal degeneration, is generally diagnosed in young adults. This condition results from progressive degeneration of the photoreceptors located in the retina (rods and cones). Initially, it mainly affects rod function: 1,000 times more sensitive to light than the cones, it is these that contribute to night vision. The most common symptom at the onset of the disease is therefore night blindness. Then, through a chain reaction[1], the cones ultimately degenerate in their turn, and patients suffer from severe sight problems from the age of 40 to 50 years.

Prevention of secondary cone degeneration is therefore a highly promising therapeutic approach. After testing the potential protective effect of 200,000 genes on the eye, Thierry Leveillard and his team demonstrated several years ago that rod-derived cone viability factor (RdCVF) directly induces survival of cones and increases their number. Results of these initial studies showed recovery of sight by patients.

In this new study, published in the journal Cell, Thierry Leveillard and his team have elucidated the mechanism of action of RdCVF on the cones: it promotes their survival by stimulating aerobic glycolysis. Aerobic glycolysis provides the cones with the substrate needed for daily renewal of part of the cone outer segment, the cell structure that carries light-sensitive molecules.

This mechanism involves several intermediaries, including the membrane protein Basigin-1, which is specifically expressed by the photoreceptors. Through the action of RdCVF, it binds to a glucose transporter that promotes the entry of glucose into the cones, which themselves metabolise glucose via aerobic glycolysis.

This highly specific type of glucose metabolism, never described for neuronal cells, is typical of malignant cells, which also proliferate and use large quantities of these metabolites.

“Since we also know that photoreceptors are retinal neurons, our work shows an entirely new neuroprotective mechanism that might affect other neurons,” predicts Thierry Leveillard, Inserm Research Director and author of this work.

“These results also contribute to our work on RdCVF. We identified this factor in 2004, with José Sahel. Its therapeutic action was then proven in animal models in 2009, and more recently in 2015. Tests that should lead to a clinical trial are underway. Understanding how RdCVF acts was indispensable in continuing to write this story of basic research and therapeutic applications.”

[1] It turns out that the rods produce a substance that allows the other category of photoreceptors, the cones, to survive. Without the rods, the cones therefore degenerate.

Drug abuse and depression: towards a new understanding of brain mechanisms

Withdrawal, experienced by people when they stop using addictive drugs such as cocaine, induces states of anxiety and depression. This process makes the individual want to take the substance again, and thus plays a role in the establishment of drug addiction. The depressive syndrome thus represents an additional obstacle to be overcome when addicts are being weaned off drugs.

To better understand the neuronal basis of such a phenomenon, an Inserm team at the Institut du Fer à Moulin (Joint Research Unit S839, directed by Dr Mameli) focused on the neurophysiological responses that follow cocaine exposure in mice. The researchers observed increased activity in the neurons of the lateral habenula projecting towards the midbrain, and the anatomical connection between these two structures is known to respond to unpleasant events. This neuronal hyperactivity is sustained, and persists for several days after initial exposure to the drug. At the same time, they observed the emergence of depressive symptoms in these mice during the withdrawal period.

By blocking this excessive neuronal activity in their mouse model, Dr Mameli and his colleagues succeeded in preventing the development of depressive behaviours that emerge during the withdrawal period.

Although additional studies are necessary prior to any clinical application, this study has made it possible to discover new potential molecular and anatomical targets for improving the negative emotional states, such as depression, that are associated with drugs.

This newly identified mechanism might be common to several affective disorders such as anhedonia—the inability to feel pleasure—and feelings of despair, which are also characterised by dysfunction of the lateral habenula.

These results need to be interpreted with caution, and cannot be considered as a solution to the risks associated with the use of addictive substances.



When breathing frees our mind

Some activities, such as walking or breathing, are unusual in that they can be carried out voluntarily or automatically. For example, every one of us can decide to take a deep breath and keep our lungs inflated for a few seconds, and then exhale slowly. However, most of the time we breathe without thinking about it, and this is what also happens every night. Although the neural structures responsible for automatic breathing, located in the brain stem, are fairly well known, those associated with voluntary breathing remain more mysterious.

Lunge mit Bronchien in grauem Umfeld

To find out more about them, Inserm researchers led by Lionel Naccache (at a joint UPMC/ICM/Inserm research centre, located within the ICM at Pitié-Salpêtrière Hospital), in collaboration with Professors Thomas Similowski and Christian Straus (Pneumology Department, Pitié-Salpêtrière Hospital and Inserm), had the idea of comparing the brain activity of a young woman affected by Ondine syndrome while she was awake and breathing voluntarily with that observed when her breathing was assisted by an external ventilator.

What is Ondine syndrome?

Infants with this mutation are born with a severe dysfunction of the brain stem structure responsible for automatic breathing. However, their voluntary breathing remains unaffected. Immediate consequence: in the most severe forms, patients die as soon as they fall asleep. Treatment involves providing these patients with external ventilators, which they use whenever they lie down, even if they are just taking a nap.

First result: when she breathed with the help of an external ventilator, her brain activity measured by functional MRI was much closer to that of a healthy subject than when she was breathing voluntarily. Conversely, in the absence of additional help, many areas of her brain were more occupied with controlling the brain stem (which in her case is unable to “steer” her breathing by itself) than with participating in the brain’s resting state network. This result is important because this network is associated with self-awareness, introspection and imagination.

Second result: this brain effort, induced by voluntary breathing, had mental or cognitive repercussions. In several cognitive tasks, the patient was shown to be more effective when she was breathing with the help of a ventilator than when she was breathing voluntarily.

These results show the automatic (brain stem) and voluntary (cortex) breathing mechanisms in a new light, and provide us with information on the cognitive impact associated with voluntary breathing. More generally speaking, these results help us to appreciate the cognitive resources that are freed up when we are breathing automatically and unconsciously.

Tactile exploration decoded

Precisely how do we distinguish the texture of objects by touch? This is what has just been decoded by a study led by Clément Léna, research director at Inserm and Daniela Popa, a researcher at Inserm in Mixed Research Unit 1024: Biology Institute, École Normale Supérieure (Inserm, ENS, CNRS) and published in the journal Nature Neuroscience. Interactions between several regions of the brain that have until now not been identified are responsible for adjusting movement and refining our sense of touch.

To achieve this result, the researcher studied the sense of touch in mice. This sense is very developed in nocturnal rodents who have a mediocre sense of sight but use their vibrissae (something like long mobile whiskers) to explore their environment by feel. In mice, the cerebral areas dedicated to sensations of touch from the vibrissae are proportionally as large as those for sensations of touch from the hands in humans. The highly sensitive vibrissae, just like the hands of primates, enable the perception of textures, forms and dimensions thanks to an extremely precise control of their movements.

souris blanches et noires

© A. Eychène / F. Bertrand (Institut Curie)

By stimulating the cerebral zones of mice using optogenetics[1], the researchers have revealed the existence of a functional circuit between the cerebellum and sensory and motor cortices. When this circuit no longer functions, mice can no longer explore their environment correctly or brush against objects in a precise manner, which changes their perception of the environment.

‘The loops of the circuit enable the cerebellum, which is a key cerebral zone, to constantly adjust the signals of the sensorimotor cortex. The movements of the body (the vibrissae in mice and fingers in humans) are then adapted in order to touch objects precisely. This is what makes us capable of distinguishing what we are touching and of perceiving the texture of a surface by stroking it, without making rough movements,’ explained Clément Léna, research director at Inserm.

The research team is now interested in the functioning of this circuit, which connects the cerebellum and the cortex, in diseases where the motor functions are altered such as Parkinson’s disease and dystonias[2]. ‘The tools that we are developing in the laboratory should make it possible to advance our understanding of these diseases and the development of symptomatic treatments,’ believes Daniela Popa, a researcher at Inserm and co-author of these projects.


Cerebral connections between the cortex and the cerebellum, enabling tactile exploration. The motor (red) and somatosensory (yellow) cortices are connected to the cerebellum (green) via the pons (green). The cerebellar nuclei (blue) project in return toward the motor cortices via the thalamus (violet). This closed loop is necessary for generating the fine movements used during tactile exploration (light touching, palpation). © Inserm/C. Léna

[1]              Technique enabling the stimulation with light of neurons that have been sensitised using genetic methods.

[2]              Diseases characterised by involuntary movements of the muscles of one or several parts of the body, often involving a torsion or distortion of this part.

L-Dopa treatment alleviates sleep disturbances associated with Parkinson’s disease

Patients suffering from Parkinson’s disease complain of severe sleep disturbances such as inability to fall asleep or, in contrast, periods of drowsiness during the day. While dopaminergic treatment dramatically improves the disease’s motor symptoms (calming tremors, for instance), its effects on sleep continued to be challenged, suggesting that the alteration of other (non-dopaminergic) neurons might be behind these other symptoms. The possible involvement of pedunculopontine nucleus (PPN) neurons, which regulate sleep and wakefulness, had been postulated in particular.

INSERM researchers working under the guidance of Chantal François (INSERM Unit 1127 /Institut du cerveau et de la moelle épinière/Université Pierre et Marie-Curie/AP-HP) have now been able to record and measure over extended periods of time, using a miniature device, the quality of sleep in animals suffering from Parkinson’s disease.

The study shows that a pure dopaminergic lesion gives rise to sleep disturbances, and that treatment using L-Dopa leads to significant improvement.

 The results show a reduction in periods of daytime drowsiness, a decrease in sudden arousal from sleep and a general increase in length of sleep.

As to the pedunculopontine nucleus, it is indeed involved in regulating the wakefulness-sleep cycle. When altered, it impacts the quality of sleep in animals with Parkinson’s disease, after causing severe but transitory disorders.

These results suggest that electrode stimulation of the pedunculopontine nucleus could be beneficial in patients with Parkinson’s disease suffering from severe sleep disturbances, as recent clinical trials show.

New risk factors for alcohol abuse in adolescents brought to light

An international team involving researchers from INSERM, CEA and APHP in France have successfully modelled the risk factors for alcohol abuse during adolescence. The results of the study were published on Nature Magazine’s website on 2 July.

In France, alcohol consumption most often begins in adolescence. Today, 80% of 17-year-olds admit to having consumed alcohol in the last 30 days. Recent studies have shown that adolescents are particularly vulnerable to the neurotoxic effects of alcohol. Early alcohol consumption has also been identified as a major risk factor in the emergence of alcohol dependence in adults.

Working under the European research project IMAGEN, dedicated to the study of risk-taking behaviours in teenagers, an international team – involving, in France, INSERM*, CEA and APHP researchers, based at I2BM – successfully modelled the risk factors for binge drinking [1] in 14-year-olds. Of relatively equal “bearing” were: life events, above all, romantic relationships; distinct brain structure and functioning in those areas involved in regulating pleasure and impulsiveness; and specific personality traits. Follow-up studies on teenagers aged 14 to 16 showed these factors to be predictors of binge drinking at age 16; in addition, their predictive value was found to be extendable to other types of alcohol abuse in adolescence. The study suggests risk factors that can be used for targeted prevention of alcoholism and is exemplary as a multi-disciplinary scientific approach to psychological disorders starting in adolescence. Nearly half of all psychiatric diseases start at this stage of life.

* INSERM – CEA 1000 Joint Unit “Neuro-Imagery and Psychiatry”

[1] The practice of consuming large amounts of alcohol in a short amount of time, in young people.

Identification of the neuronal network that controls our actions and errors

When we perform an action for a specific purpose, or in response to a stimulus, it is imperative that we be able to correct it while carrying it out if it turns out to be inappropriate. Such an ability affects the quality of our daily lives, both in our immediate motor activity (not “running” a traffic light when it turns red, etc.), and in our social behaviour (attitudes that suit the circumstances). Researchers from CNRS, Inserm and Aix-Marseille University have just identified the neuronal network that controls our actions and detects our errors. By directly recording activity in the cerebral cortex of patients undergoing exploratory brain surgery, the researchers were able to discover that an area of the frontal cortex (the Supplementary Motor Area or SMA) is the node in the network that evaluates our actions and detects errors. In this article, published in Science on 21 February 2014, the researchers specify the brain circuits involved in this self-assessment of our actions, as well as its mechanics and its relationship with the detection of erroneous behaviours in relation to our intentions.

inserm_12942© Inserm