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.

Spermatozoa losing speed

Infertility affects between 7% and 12% of couples worldwide. The causes of male infertility include several defects of the sperm including asthenozoospermia. This is a deficiency in the motility of spermatozoa, an essential ingredient for an encounter between the sexual cells during reproduction. Asthenozoospermia, detected in more than 40% of infertile men, is often associated with low sperm production during male ejaculation and morphological anomalies (which are known as  oligoasthenoteratozoospermia [1]).

The research group headed by Dr Aminata Touré of the Inserm team 1016 “Genomics, epigenetis and physiopathology of reproduction” of the Cochin Institute (INSERM / CNRS / Université Paris Descartes) studied the genetic component of this condition, one about which little is known despite the strong prevalence associated therewith.

In this study published in The American Journal of Human Genetics, the researchers showed that for several subjects, in an initial cohort of 146 patients presenting with asthenozoospermia, there were deleterious mutations of the SLC26A8 gene.

This gene code is for a transporter exclusively expressed in the spermatozoa. The mutations identified produce functional alterations in the transporter involved in the regulation of the interaction between spermatozoa and the external environment. A change in such interaction prevents the spermatozoa from moving correctly towards the ovule in the female genital tract. Very few genes have so far been identified that are capable of playing a decisive role in sperm mobility and its activation.

“Our work opens up the prospect of better knowledge of the genetic causes of human asthenozoospermia”, explains Aminata Touré, head of research and manager of the study. “This will eventually make it possible to offer genetic counselling for couples seeking help with infertility and wanting to have children through Medically Assisted Procreation (MAP) techniques,” she concluded.


Photo de une : ©Fotolia

[1] From oligo = few    astheno = not very mobile and  terato=  with atypical forms

Genetic mutation and the prognosis for renal polycystosis

The team headed by Claude Férec, director of INSERM 1078 “Genetics, functional genomics and biotechnologies” (INSERM/Université de Bretagne/EFS) in Brest, published results in the Journal of the American Society of Nephrology from a cohort of 700 patients suffering from Autosomal Dominant Polycystic Kidney Disease (ADPKD). This condition, the most frequent monogenetic hereditary kidney disease, manifests through the slow and progressive appearance of cysts, mainly on the kidneys.

Researchers showed from the Genkyst cohort that the type of mutation that affects the genes in question in the manifestation of the illness is strongly associated with kidney survival. The median age for terminal renal failure in the illness is 12.3 years earlier when it involves a deleterious mutation in the PKD1 gene, i.e. when all or part of the protein is missing. This type of mutation disrupts the gene’s ability to read which it needs for the long process terminating in the synthesis of proteins. The average age of patients who have reached the terminal renal stage is thus 55.6 years compared to 67.9 years for those not presenting with this type of mutation and 79 years for those with the mutation in the PKD2 gene.

A complete molecular analysis of the PKD1 and PKD2 genes in question enabled Claude Férec’s team, in the context of a project implemented in collaboration with the team headed by Yannick Le Meur, to identify a mutation in 93% of the patients in the cohort.

“Genkyst makes it possible to better establish a relationship between patients’ genotype and phenotype and shows for the first time that the genetic mutation in this illness has a major impact on the way renal function alters over time,”

 concludes Claude Férec, principal author of the study.

Advances in Friedreich’s Ataxia

Friedreich’s ataxia is a rare, serious and developing neurodegenerative condition that emerges at adolescence. Those affected suffer from difficulties in coordinating voluntary movements (ataxia). This is the commonest of the hereditary ataxias of genetic origin and occurs due to a mutation of the fraxatin gene which causes a protein deficiency.

The team headed by Alexandra Henrion Caude, responsible for INSERM research in the 781 Mixed Unit known as “Genetics and epigenetics of metabolic, neuro-sensorial and developmental diseases” (INSERM, Université Paris Descartes) at the Necker Children’s Hospital, explored the possibility that other elements in the gene could contribute to this deficiency, as a way of understanding the disturbed relationship between the gene mutation and the frataxin protein levels measured in certain patients.

The researchers discovered, as shown in the study published recently in the journal Plos One, through research performed in synergy with the French Freidreich’s Ataxia Association (AFAF), that the patients had fraxatin gene variations that were specific to them. They showed the involvement of micro-RNA, especially miR-124, in the regulation of the expression of the frataxin protein. To achieve this result, the researchers analysed data from a cohort of patients suffering from Friedreich’s ataxia, and these were compared with the genetic data from people not suffering from the condition. They confirmed their results via an analysis of a second cohort from the island of Réunion, whose data are particularly interesting for geneticists due to their geographic isolation.

According to the study’s authors, these results promise to produce a more precise genetic profile of patients to improve diagnosis and prognosis. They suggest above all that the inhibition of certain micro-RNAs, especially miR-124, could constitute a route for the development of therapies to restore the deficient protein that appears to be the cause of this serious illness.

This study was the subject of an application to file a patent submitted by Inserm Transfert.

The French Friedreich’s Ataxia Association , the AFAF, has been in existence for more than 30 years. It has 800 members of whom 500 are sufferers. The three main aims of the Association are to stimulate research in partnership with research teams and the Conseil Scientifique since to date there is no cure, improve the care of ataxic patients through information for carers in collaboration with the Conseil Médical et Paramédical, and provide support for patients and their families through meetings, links and especially a psychological support service. More information can be found on the Association’s site

The origin of blindness identified for some types of hearing loss and visual impairment

Researchers from the Institut Pasteur, the Institut de la Vision, Inserm and the Université Pierre et Marie Curie have shed light on the origin of blindness that occurs in Usher I (the most common cause of deafness-blindness in humans). The scientists also demonstrated why the rat, the only animal model available today for this illness, does not suffer from the same blindness observed in humans. This work involves directing future research towards producing a primate animal model. The latter will then make it possible to progress towards a therapy-based approach for blindness in patients suffering from Usher I. This research was published on 8 October in the Journal of Cell Biology.

Usher syndrome is a genetic illness that causes congenital deafness and progressive visual impairment caused by retinitis pigmentosa. The prevalence rate of Usher syndrome is estimated at 1/30,000. Currently, a good level of care is provided for patients with hearing disorders. However, today, there is no treatment able to stop the end result of retinitis pigmentosa.

Research conducted by Professor Christine Petit, head of the “Genetics and physiology of hearing” research unit at the Institut Pasteur, in collaboration with Dr Aziz El-Amraoui (Institut Pasteur) and Professor José-Alain Sahel (Institut de la Vision), has provided fresh grounds for hope: researchers have just discovered the origin of retinitis pigmentosa in patients suffering from Ushers  I. It stems from a fault in the organization of cell structures essential to maintain vision, calyceal processes.  This failure is caused by the malfunction of one or several proteins; in this case, five were identified by the researchers that ensured cohesion in the calyceal processes. It was possible to observe the structure of the calyceal processes in high definition using electronic microscopic techniques (see photos).

For more information

©Copyright Institut Pasteur / Cataldo Schietroma et Vincent Michel