Alpha-synuclein is a neuronal protein that regulates synaptic vesicle trafficking and subsequent neurotransmitter release. alpha-synuclein aggregates to form insoluble fibrils in pathological conditions characterized by Lewy bodies, such as Parkinson's disease, dementia with Lewy bodies and multiple system atrophy.

It is abundant in the brain, while smaller amounts are found in the heart, muscle and other tissues. In the brain, alpha-synuclein is found mainly at the tips of neurons in specialized structures called presynaptic terminals.

The accumulation of α-synuclein (α-Syn) aggregates that leads to the onset of Parkinson's disease (Parkinson's disease) has been postulated to begin in the gastrointestinal tract. The normal human appendix contains pathogenic forms of α-Syn, and appendectomy has been reported to affect the incidence of Parkinson's disease.

In 2007, Braak and co-authors advanced a ‘dual-hit hypothesis’ about the pathogenesis of idiopathic Parkinson's disease, according to which an unknown pathogen akin to a slow-virus may enter the nervous system through both the nasal and intestinal mucosae, eventually resulting in a cascade of neurodegenerative events in the brain.

In 2018 Killinger, Labrie and colleagues reported that in two independent epidemiological datasets, involving more than 1.6 million individuals and over 91 million person-years, they observed that removal of the appendix decades before PD onset was associated with a lower risk for PD, particularly for individuals living in rural areas, and delayed the age of PD onset.

After studying 48 subjects without Parkinson disease, they also found that the healthy human appendix contained intraneuronal α-synuclein aggregates and an abundance of PD pathology–associated α-synuclein truncation products that are known to accumulate in Lewy bodies, the pathological hallmark of PD.

In this new study by Yuhua Chen, Feng Yu and colleagues in University of Science and Technology of China in Hefei, investigated appendix abnormality in patients with Parkinson's disease.

The scientists assessed appendix morphology in 100 patients with Parkinson's disease and 50 control subjects by multislice spiral computed tomography. They analyzed the clinical characteristics of patients with Parkinson's disease with diseased appendices, which was confirmed in seven patients by histopathological analysis.

Chronic appendicitis-like lesions were detected in 53% of patients with Parkinson's disease, but these were not associated with the duration of motor symptoms.

Appendicitis-like lesions, impaired olfaction, and rapid eye movement sleep behavior disorder are known risk factors for Parkinson's disease.

The seven patients with Parkinson's disease who were diagnosed with chronic appendicitis underwent appendectomy, and histopathological analysis revealed structural changes associated with chronic appendicitis and α-Syn aggregation.

These results indicate an association between chronic appendicitis-like lesions and Parkinson's disease, and suggest that α-Syn accumulation in the diseased appendix occurs in Parkinson's disease. The appendix may play a role in the pathogenesis of Parkinson's disease, but the exact mechanism remains unclear. The appendix could be a source of pathological α-syn that propagates to the central nervous system, but a “second-hit” may be required for this phenomenon to occur. Factors like chronic inflammation, microbiome perturbations, formation of α-syn truncation products, and impaired cellular clearance of α-syn aggregates may serve to promote the generation and spread of pathology from the appendix to the brain. The vagus nerve, compromised BBB integrity, and/or age-dependent degeneration of the CNS lymphatic system may be routes by which α-syn seeds accumulate in the brain.

Alternatively (or in addition), immunosurveillance functions of the appendix may contribute to acquiring autoimmunity towards α-syn, including the generation of self-reactive T cells and autoantibodies. Hence, studying the accumulation and possible spreading of α-syn from appendix to brain could help our understanding of the origins of Parkinson's disease.

An international clinical trial, is investigating whether infrared light can improve symptoms of Parkinson's disease. The experimental results, based on preclinical studies, indeed suggest that brain illumination in the near infrared is likely to slow down this neurodegenerative disease.

Hamilton, Mitrofanis and others had previously reported that wearing headphones equipped with infrared LEDs improved quality of life, although it did not have much effect on motor symptoms.

A medical device system (called Ev-NIRT) has been developed by the French scientists and Boston Scientific Corporation, for intracerebral illumination at 670 nm of the black substance pars compacta (SNpc), and will be tested in this pilot study.

Researchers will assess the feasibility and tolerance of surgery and brain illumination using the Ev-NIRT medical device, in a group of 7 patients with Parkinson's disease in whom the innovative medical device will be implanted. The patients will be followed for 4 years. The device will emit pulses at a wavelength of 670 nm for one minute, with a periodicity of 150 Hz. This burst of pulses will be followed by five minutes of rest.

The team, led by neurosurgeon Alim-Louis Benabid of the Clinatec Institute, hopes that exposing this area of ​​the brain to infrared light will protect cells from death. Benabid, along with Pierre Pollak, are the pioneers who developed deep brain stimulation (DBS) in 1987. DBS works by sending electrical impulses into the brain. This invention has changed the lives of thousands of patients, but it has long term side effects.

About ten years ago, John Mitrofanis, a neuroanatomist at the University of Sydney, spent a year studying DBS with Benabid with the aim of creating a similar concept, but using infrared light. Mitrofanis was inspired by infrared headsets, used in the Parkinson's community.

Benabid and Mitrofanis, however, felt that light from outside the skull would not penetrate deep enough and that an implantable device had to be created. In 2017, in collaboration with researcher Cécile Moro, they injected 20 macaques with a neurotoxin present in certain recreational drugs (MPTP) and known to cause the symptoms of Parkinson's disease. Scientists exposed nine macaques to near infrared in the midbrain region using an implanted device.

The French study will follow 14 patients with early-stage Parkinson's disease for 4 years, seven of whom will be treated periodically with 670 nanometer pulses of light delivered to the brain via a thin laser diode cable. The other seven patients will not be operated on; an ethics review committee has in fact decided not to subject them to surgery without the possibility of benefit.

Some Parkinson's researchers are skeptical. No one has shown why exposure to infrared should have an effect on cells that never see daylight. Neurons do not have a chlorophyll-based metabolism. Much of the encouraging results seen so far may be the result of the placebo effect, skeptics say.

There are three main hypotheses to explain how photomodulation works.

• The first recalls that molecules sensitive to light in the body called chromophores are excited by photon stimulation. We now know that hemoglobin, myoglobin and COX are the only 3 chromophores in mammalian tissues capable of absorbing near infrared light (wavelength 600 to 900 nm). However, there is no clear mechanism of action linking these chromophores to the increased ATP synthesis which is observed under light stimulation.

• The second hypothesis explains that the production of mitochondrial energy is the effect of a reduction in the intra-mitochondrial viscosity of water induced by the near infrared. the reduction in near infrared mediated viscosity decreases the friction that opposes the rotation of ATP synthase and results in a "smoother" rotation of the ATP synthase machinery. This theory is supported by the fact that increases in cellular ATP level are immediate after near infrared stimulation.

• A third hypothesis suggests that the photoabsorbent pyropherophorbide-a (P-a) metabolite of dietary chlorophyll may facilitate light energy production processes in animals. In the experiments, ATP levels increased only in groups where P-a and near infrared light were co-administered, and not in those where P-a or near infrared were administered in isolation. Given the multiplicity of these competing theories, it is possible that the near infrared exerts its modulatory effects through several mechanisms instead of just one.

The main aim of this new clinical study is to prove that the implant is safe, says Benabid, but the researchers will also assess the progression of the disease. “This must lead to a great improvement,” he says. "There would be no reason to have extensive surgery for only slight improvement."

The major problem with all neuroprotection trials in Parkinson's disease is that diagnosis appears to occur after more than 50% of the dopamine-producing cells have disappeared. Unless the improvement is huge, the signal will be too weak to be detected.

The team will also be looking for clinical benefits. But because researchers assess symptoms of Parkinson's disease by observing patients performing specific tasks, the assessments are largely subjective and symptoms vary over time; everyone has good days and bad. Since the control group will not undergo surgery, it will be particularly difficult to rule out placebo effects.

Un essai clinique international, mais initié depuis la France cherche à savoir si la lumière infrarouge peut améliorer les symptômes de la maladie de Parkinson. Les résultats expérimentaux, basés sur des études précliniques, suggèrent en effet que l'illumination cérébrale dans le proche infrarouge est susceptible de ralentir cette maladie neurodégénérative. Hamilton, Mitrofanis et d'autres avaient précédemment rapporté que le port d'un casque équipé de LEDs infrarouges améliorait l'expression faciale, le traitement auditif, l'engagement dans la conversation, la qualité du sommeil et la motivation, bien que cela n'ait pas eu beaucoup d'effet sur les symptômes moteurs. Ann Liebert de l'Université de Sydney prévoit une étude chez 120 patients utilisant un casque plus sophistiqué.

Un système de dispositif médical (appelé Ev-NIRT) a été développé pour un éclairage intracérébral à 670 nm de la substance noire pars compacta (SNpc), et sera être testé dans cette étude pilote. Les chercheurs évalueront la faisabilité et la tolérance de la chirurgie et de l'illumination cérébrale grâce au dispositif médical Ev-NIRT, auprès d'un groupe de 7 patients atteints de la maladie de Parkinson auquels sera implanté le dispositif médical innovant. Les patients seront suivis pendant 4 ans. L'appareil émettra pendant une minute des impulsions à une longueur d'onde de 670 nm, avec une périodicité de 150 Hz. Cette salve d'impulsions sera suivie de cinq minutes de repos.

L'équipe, dirigée par le neurochirurgien Alim-Louis Benabid de l'Institut Clinatec espère que l'exposition de cette zone du cerveau à la lumière infrarouge protégera les cellules de la mort. Benabid avec Pierre Pollak, sont les pionniers qui ont développé la stimulation cérébrale profonde (DBS) en 1987. DBS fonctionne en envoyant des impulsions électriques dans le cerveau. Cette invention a changé la vie de milliers de patients, mais elle a des effects secondaires à long terme.

Il y a une dizaine d'année, John Mitrofanis, neuro-anatomiste à l'Université de Sydney, avait passé un an à étudier le DBS avec Benabid dans le but de créer un concept similaire, mais utilisant la lumière infrarouge. Mitrofanis était inspiré par les casques à infrarouge, utilisés dans la communauté Parkinson.

Benabid et Mitrofanis ont cependant estimé que la lumière provenant de l'extérieur du crâne ne pénétrerait pas assez profondément et qu'il fallait créer un dispositif implantable. En 2017, en collaboration avec la chercheuse Cécile Moro, ils ont injecté à 20 macaques une neurotoxine présente dans certaines drogues récréatives (MPTP) et connue pour provoquer les symptômes de la maladie de Parkinson. Les scientifiques ont exposés neuf macaques à du proche infrarouge dans la région du mésencéphale grâce à un dispositif implanté.

L’étude française suivra 14 patients atteints de la maladie de Parkinson à un stade précoce pendant 4 ans, dont sept seront traités périodiquement avec des impulsions de lumière de 670 nanomètres délivrées au cerveau via un mince câble à diode laser. Les sept autres patients ne seront pas opérés; un comité d'examen éthique a en effet décidé de ne pas les soumettre à une intervention chirurgicale sans possibilité de bénéfice.

Certains chercheurs sur la maladie de Parkinson sont sceptiques. Personne n'a montré pourquoi l'exposition à de l'infrarouge devrait avoir un effet sur des cellules qui ne voient jamais la lumière du jour. Les neurones n'ont pas un métabolisme basé sur la chlorophyle. Une grande partie des résultats encourageants observés jusqu'à présent peuvent être le résultat de l'effet placebo, disent les sceptiques.

Il existe trois hypothèses principales pour expliquer le fonctionnement de la photomodulation.

• La première rappelle que les molécules sensibles à la lumière du corps appelées chromophores sont excitées par stimulation photonique. On sait maintenant que l'hémoglobine, la myoglobine et la COX sont les 3 seuls chromophores dans les tissus des mammifères capables d'absorber la lumière dans le proche infrarouge (longueur d'onde de 600 à 900 nm). Cependant, il n'y a pas de mécanisme d'action clair liant ces chromophores à l'augmentation de la synthèse d'ATP qui est observée sous stimulation lumineuse.

• La deuxième hypothèse explique que la production d'énergie mitochondriale est l'effet d'une réduction de la viscosité intra-mitochondriale de l'eau induite par le proche infrarouge. la réduction de la viscosité à médiation proche infrarouge diminue le frottement qui s'oppose à la rotation de l'ATP synthase et entraîne une rotation «plus douce» de la machinerie de l'ATP synthase. Cette théorie est étayée par le fait que les augmentations du niveau d'ATP cellulaire sont immédiates après la stimulation au proche infrarouge.

• Un troisième hypothese suggére que le métabolite photo-absorbant pyrophéophorbide-a (P-a) du chlorophyl alimentaire pourrait faciliter les processus de production d'énergie par la lumière chez les animaux. Dans les expériences, les niveaux d'ATP n'ont augmenté que dans les groupes où P-a et la lumière proche infrarouge étaient co-administrés, et non dans ceux dans lesquels P-a ou proche infrarouge étaient administrés isolément. Compte tenu de la multiplicité de ces théories concurrentes, il se peut que le proche infrarouge exerce ses effets modulateurs à travers plusieurs mécanismes au lieu d'un seul.

L'objectif principal de cette nouvelle étude clinique est de prouver que l'implant est sûr, dit Benabid, mais les chercheurs évalueront également la progression de la maladie. «Cela doit induire une grande amélioration», dit-il. «Il n'y aurait aucune raison de faire une intervention chirurgicale étendue pour une amélioration qui ne serait que légère.»

Le problème majeur de tous les essais de neuroprotection dans la maladie de Parkinson est que le diagnostic semble se produire après la disparition de plus de 50% des cellules productrices de dopamine. À moins que l'amélioration ne soit énorme, le signal sera trop faible pour être détecté.

L'équipe recherchera également des avantages cliniques. Mais comme les chercheurs évaluent les symptômes de la maladie de Parkinson en observant les patients effectuant des tâches spécifiques, les évaluations sont largement subjectives et les symptômes varient dans le temps; tout le monde a de bons et de mauvais jours. Étant donné que le groupe témoin ne subira pas de chirurgie, il sera particulièrement difficile d'exclure les effets placebo.

Parkinson's disease is a common neurodegenerative disease. Although the exact etiology and natural course of this disease have yet to be fully clarified, numerous system-level processes and dysfunctions, have been implicated in the pathogenesis of Parkinson's disease.

Lipid droplets are highly dynamic organelles that emerge from the endoplasmic reticulum (ER) membrane. lipid droplets is involved in fatty acid storage and participate in many diseases. For example, myeloid cells, including macrophages, leukocytes, and eosinophils, form lipid droplets in response to inflammation and stress.

Normally, intracellular lipid droplets are degraded in lysosomes and deliver fatty acids to mitochondria for their consumption as an alternative energy source during periods of nutrient depletion. However, neurons have a low capacity for mitochondrial fatty acid consumption for energy production. This characteristic makes neurons particularly sensitive to lipid droplet accumulation and peroxidation.

Furthermore, the accumulation of lipid droplets enhances the fatty acid oxidation rate and imposes persistent pressure on the mitochondrial electron transport chain. Lipid overload also leads to ROS production by oxidative enzymes. Emerging evidence indicates that unexpected lipid droplet deposition and peroxidation can accelerate organelle stress and plays a crucial role in the pathogenesis of neurodegenerative diseases.

In a previous study, Xiaojuan Han and colleagues found that kaempferol, a natural flavonoid small molecule, exhibited neuroprotective effects on mice with drug-induced Parkinson's disease.

In the current study, the authors showed in-vitro that kaempferol protected against tyrosine hydroxylase neuronal loss and behavioral deficits in methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP) induced Parkinson disease mice, accompanied by reduced lipid oxidative stress in the substantia nigra pars compacta.

Kaempferol-rich food has been linked to a decrease in the risk of developing some types of cancers and cardiovascular disease. Quercetin and kaempferol are among the most ubiquitous polyphenols in fruit and vegetables.

Kaempferol is a chemical produced by Kaempferia galanga, one of four plants called galangal. The extract of Kaempferia galanga causes central nervous system depression, a decrease in motor activity, and a decrease in respiratory rate.

The mice were treated with kaempferol. The rotarod performance time was markedly reduced in MPTP-treated mice, and this effect was prevented by kaempferol. kaempferol also restored the behavioral deficits induced by MPTP, as indicated by the reductions in the turning time and total time in the pole test, without affecting the body weights of the mice.

MPP+, the active metabolite of MPTP, inhibits mitochondrial complex enzymes and causes the cell death that is directly associated with PD. In cultured neuronal cells, kaempferol exhibited a relatively safe concentration range and significantly suppressed lipid droplet accumulation and cellular apoptosis induced by MPP.

Further studies indicated that the protective effect of kaempferol was dependent on autophagy, specifically lipophagy. Critically, kaempferol promoted autophagy to mediate lipid droplet degradation in lysosomes, which then alleviated lipid deposition and peroxidation and the resulting mitochondrial damage, consequently reducing neuronal death.

Furthermore a genetic knockdown abolished the neuroprotective effects of kaempferol against lipid oxidation in Parkinson disease mice.

This work demonstrates that kaempferol prevents dopaminergic neuronal degeneration in Parkinson disease via the inhibition of lipid peroxidation-mediated mitochondrial damage by promoting lipophagy and provides a potential novel therapeutic strategy for Parkinson disease and related NDDs.

Parkinson’s disease (Parkinson’s disease) is a major neurodegenerative disorder. It currently lacks a clinically relevant treatment that can directly target the disease-causing processes. Current clinical approaches, like deep brain stimulation and pharmacological treatments with levodopa and dopamine agonists, only relieve symptoms. The efficacy of these treatments is largely limited by their undesirable complications and side effects. Source: By Ajpolino via Wikipedia

Since α-synuclein is overexpressed under certain pathological conditions of PD and these upregulated proteins can interfere with many physiological processes, such as ER-to-Golgi transport, synaptic transmission, and mitochondria function and morphology, robustly knocking down the overexpressed α-synucleinmay have better neuroprotective efficacy in restoring normal cellular functions in the Parkinson’s disease brain than simply inhibiting the formation of toxic α-synuclein oligomers.

Knockdown of α-synuclein using genetic manipulations, such as antisense oligonucleotide and small interfering RNA (siRNA), has shown protection of dopaminergic neurons in various models of Parkinson’s disease.

The clinical translation of these manipulations into an efficient Parkinson’s disease therapy has however costly and uncomfortable, as it is mainly accomplished by an invasive injection or viral infection. These technologies may not be clinically practical for therapeutic use in human patients.

Here the scientists report the development of a short, BBB and plasma membrane-permeant synthetic peptide that can rapidly reduce endogenous α-synuclein via proteasomal degradation.

Using both in vitro and in vivo models of Parkinson’s disease, the scientists provide proof-of-principle evidence for using this small α-synuclein knockdown peptide as a potential Parkinson’s disease therapy.

The authors first demonstrated that the Tat-βsyn-degron peptide can specifically reduce the level of α-synuclein both in vitro and in vivo. The authors then showed that the peptide-induced α-synuclein knockdown is associated with protection of dopaminergic neurons against toxin-induced damage in a culture model of Parkinson’s disease.

Most importantly, the scientists were able to demonstrate the therapeutic potential of systemic application of the Tat-βsyn-degron peptide as an effective Parkinson’s disease treatment in two well-characterized animal models of Parkinson’s disease.

Their α-synuclein knockdown peptide (Tat-βsyn-degron) is innovative as the peptide directly targets one of the disease-causing processes, and can be expected to stop or slow down the progression of the disease.

In addition, the peptide-mediated knockdown has a clear temporal advantage over antisense or siRNA-mediated knockdown. α-synuclein is a very stable protein with a long half-life while by hijacking the endogenous proteasomal degradation system in the cell, the Tat-βsyn-degron peptide produced a rapid and robust degradation of α-synuclein protein within a few hours.

It is also interesting to note that α-synuclein is also expressed in tissues outside the central nervous system and the scientists found that a single intraperitoneal injection of the Tat-βsyn-degron peptide similarly reduced the α-synuclein expression in the kidney and the spleen of wild-type C57BL/6 mice .

A recent success in a phase 3 clinical trial has already demonstrated that a Tat-fused short peptide is not only safe, but therapeutically effective in protecting neurons against ischemic damage in humans. The authors hope this α-synuclein knockdown peptide may also have the potential to be quickly translated into the clinic as an effective disease-modifying treatment that directly targets the disease-causing process of Parkinson’s disease.

Due to the versatility of their peptide-mediated protein knockdown method, the scientists can theoretically target disease-causing cellular proteins by simply changing the protein-binding sequence of the targeting peptide. Since many human diseases, including some of the age-related neurodegenerative diseases such as ALS, Alzheimer’s disease and Huntington’s disease, are pathologically caused by gain of function of a protein due to its mutations and/or increased expression levels, the proposed study can be expected to spur the development of new therapeutics for human diseases beyond Parkinson’s disease.

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A study which has just been published in the leading neurology journal Brain, indicates that Parkinson's disease is not one but two diseases, starting either in the brain or in the intestines.

These two groups of patients displayed strikingly different profiles on multimodal imaging battery.

These profiles support the existence of a brain-first and body-first subtype of Parkinson’s disease, and furthermore, that premotor rapid eye movement sleep (REM) sleep behaviour disorder is a highly predictive marker of the body-first subtype.

Neuropathological autopsy studies of patients with Parkinson’s disease, dementia with Lewy bodies, or incidental Lewy body disease have shown discrepant results.

Heiko Braak’s staging system was derived from a cohort of patients, who were selected based on the presence of Lewy pathology in the dorsal motor nucleus of the vagus, and all these patients conformed to a brainstem predominant type.

Other studies reported that some post-mortem cases do not harbour Lewy pathology in the dorsal motor nucleus of the vagus, and a minority of patients do not follow the Braak staging scheme.

A pathological hallmark of Parkinson’s disease is the presence of intraneuronal a-synuclein inclusions termed Lewy pathology. However, it remains unknown from where the initial a-synuclein aggregates originate.

It has been hypothesized that a-synuclein inclusions initially form in nerve terminals of the enteric nervous system, and then subsequently spread via autonomic connections to the dorsal motor nucleus of the vagus and intermediolateral cell columns of the sympathetic system (Braak et al., 2003).

In addition, Lewy pathology has been detected in gastrointestinal nerve fibres years prior to Parkinson’s disease diagnosis. There is also epidemiological evidence that complete but not partial vagotomy may protect against later Parkinson’s disease.

Autopsy studies have shown that a minority of cases with Lewy pathology do not have pathological inclusions in the dorsal motor nucleus of the vagus, and that a fraction of cases display a limbic-predominant distribution of a-synuclein inclusions with less pathology in the brainstem.

The scientists hypothesized that the appearance of isolated REM sleep behaviour disorder well before parkinsonism is a strong marker of the body-first subtype. The presence of REM sleep behaviour disorder in the premotor phase is a marker of the body-first type, probably a reflection of ascending a-synuclein pathology reaching the pons before the substantia nigra. The substantia nigra in the brain. Source Wikipedia

To test this hypothesis, they recruited de novo patients with Parkinson’s disease and performed video-polysomnography to divide patients into de novo Parkinson’s disease without REM sleep behaviour disorder and de novo Parkinson’s disease with pre-motor REM sleep behaviour disorder. The study was conducted between August 2018 and January 2020.

The scientists have shown that prodromal and de novo patients with Parkinson’s disease can be categorized by means of multimodal imaging into distinct clusters, which are compatible with a brain-first and body-first Parkinson’s disease subtype.

Their conclusion is that the Parkinson’s disease comprises two subtypes: (i) a body-first (bottom-up) subtype, where the pathology originates in the enteric or peripheral autonomic nervous system, and then ascends via the vagus nerve and sympathetic connectome to the CNS;

(ii) a brain-first (top-down) subtype, in which the a-synuclein pathology initially arises in the brain itself or sometimes enters via the ol- factory bulb, and subsequently descends to the peripheral autonomic nervous system.

Body-first (bottom-up) subtype: The initial a-synuclein pathology appears in the enteric or peripheral autonomic nervous system. It then propagates via the sympathetic connectome to the heart, and via the vagus nerve to the dorsal motor nucleus of the vagus. The pons area in the brain. Source Wikipedia

Ascending pathology affects pontine structures giving rise to REM sleep behaviour disorder before the substantia nigra shows substantial involvement. When parkinsonism appears, signifying a loss of 450% of nigrostriatal dopamine terminals, all lower Braak stage structures show marked damage on relevant imaging markers.

Brain-first (top-down) subtype: In the brain-first type, the initial a-synuclein pathology appears in the CNS. The most likely site of origin seems to be the amygdala or connected structures, or the pathology may in some cases enter via the olfactory bulb. Rarely, the pathology arises in the upper brainstem (substantia nigra or locus coeruleus). The pathology spreads from the site of origin to the brainstem and cortex. When parkinsonism appears, the brainstem shows a rostro-caudal gradient of pathology with marked involvement of the substantia nigra, moderate involvement of the neighbouring pons, but little involvement of the medulla and autonomic nervous system.

Citation: Jacob Horsager et al, Brain-first versus body-first Parkinson's disease: a multimodal imaging case-control study, Brain (2020). DOI: 10.1093/brain/awaa238

Parkinson's disease is characterized by a loss of dopaminergic neurons in the substantia nigra. There is no treatment that can improve the course of Parkinson's disease. While most treatment strategies are aimed at preventing neuronal loss or protecting neural circuits, a potential alternative, is to replace lost neurons to reconstruct altered neural circuits.

Given the plasticity of some somatic cells, transdifferentiation approaches to change the fate of cells (in situ as escape the immune system) have gained momentum. In the brain of mice, the plasticity of glial cells has thus been used to generate new neurons which have shown an improvement in disease in model animals.

Most in vivo reprogramming relies on the use of transcription factors specific to the cell line under consideration. This study shows that there are other ways to achieve this goal.

Researchers from the University of California (UC), San Diego School of Medicine, have developed a non-infectious virus that carries an antisense oligonucleotide sequence designed to specifically bind to RNA encoding the PTB protein, degrading it, preventing it from being translated into a functional protein. Antisense oligonucleotides are a proven therapeutic approach.

Sequential downregulation of PTB and nPTB occurs naturally during neurogenesis, and once triggered, the gene expression loops regulated by PTB and nPTB become self-reinforcing. By modulating the two loops, the sequential negative regulation of PTB and nPTB makes it possible to generate functional neurons from human fibroblasts.

Astrocytes offer several benefits for in vivo reprogramming in the brain. These non-neuronal cells are abundant, proliferate when injured and are very plastic. They can adopt different phenotypes or even be reprogrammed in a very different cell type. Astrocytes can be converted into different neural subtypes, depending on their region of origin in the brain.

Here, scientists from the University of California, San Diego School of Medicine, report an efficient, single-step conversion of astrocytes from humans and mice into functional neurons. This by depleting the RNA-binding protein PTB (also known as PTBP1).

The target cells for this conversion are the dopaminergic neurons in the substantia nigra, that is, those that become non-functional in Parkinson's disease. Using this approach, the team demonstrated the gradual conversion of astrocytes into new neurons capable of innervating and repopulating the neural circuits of the substantia nigra. These dopaminergic neurons induced by depletion of the PTB powerfully restore striatal dopamine, restore the nigrostriatal circuit and reverse the motor phenotypes of Parkinson's disease.

In treated mice, a subset of about 30% of the astrocytes were converted to neurons, thus increasing the total number of neurons. Dopamine levels were restored to a level comparable to that of normal mice. In addition, neurons have developed and sent their processes to other parts of the brain. There was no change in the control mice.

The treated mice recovered their vitality with a single treatment and remained completely free of Parkinson's symptoms for the rest of their lives. In contrast, control mice did not show any improvement.

To experiment with the conversion of midbrain astrocytes to dopaminergic neurons, the scientists used a model of chemically induced Parkinson's disease in mice. The model used by the team does not perfectly summarize all the essential characteristics of Parkinson's disease. In the future, scientists will use a more expensive animal genetic model of Parkinson's.

One could wonder if this therapy can be transposed to other neurodegenerative diseases. However, Parkinson's disease is characterized by an illness in a very specific region of the brain. On the contrary, in Alzheimer's disease, the damage is global to the brain and in the case of amyotrophic lateral sclerosis the neurons involved are the motor neurons, but they cover a considerable area.

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La maladie de Parkinson se caractérise par une perte de neurones dopaminergiques dans la substantia nigra. Il n’existe aucun traitement pouvant améliorer le cours de la maladie de Parkinson. Alors que la plupart des stratégies de traitement visent à prévenir la perte neuronale ou à protéger les circuits neuronaux, une alternative potentielle, mais non explorée jusqu’à maintenant, consiste à remplacer les neurones perdus pour ainsi reconstruire les circuits neuronaux altérés.

Compte tenu de la plasticité de certaines cellules somatiques, les approches de transdifférenciation pour changer le destin des cellules (in situ pour échapper au système immunitaire), ont pris de l’ampleur. Dans le cerveau de souris, la plasticité des cellules gliales a ainsi été mise à profit pour générer de nouveaux neurones ayant montrés une amélioration de maladie chez les animaux modèles.

La plupart des reprogrammations in vivo reposent sur l’utilisation de facteurs de transcription spécifiques à la lignée de cellule considérée. Cette étude montre qu’il existe d’autres moyens pour atteindre cet objectif.

Des chercheurs de l'Université de Californie ont développé un virus non infectieux qui porte une séquence d’oligonucléotides antisense conçue pour se lier spécifiquement à l’ARN codant pour la protéine PTB, la dégradant ainsi, l’empêchant d’être traduit en une protéine fonctionnelle. Les oligonucléotides antisense sont une approche thérapeutique éprouvée.

La régulation négative séquentielle de PTB et nPTB se produit naturellement pendant la neurogenèse, et une fois déclenchée, les boucles d’expression génique régulées par PTB et nPTB deviennent auto-renforçantes. En modulant les deux boucles, la régulation négative séquentielle de PTB et nPTB permet de génèrer des neurones fonctionnels à partir de fibroblastes humains.

Les astrocytes offrent plusieurs avantages pour la reprogrammation in vivo dans le cerveau. Ces cellules non neuronales sont abondantes, prolifèrent en cas de blessure et sont très plastiques. Elles peuvent adopter différents phénotype, voire être reprogrammées dans un type de cellule très différent. Les astrocytes peuvent être convertis en différents sous-types neuronaux, suivant leur région d’origine dans le cerveau.

Ici, les scientifiques rapportent une conversion efficace en seule étape, d’astrocytes issus d’humains et de souris, en neurones fonctionnels. Ceci en appauvrissant la protéine de liaison à l’ARN PTB (également connue sous le nom de PTBP1). Les cellules cibles de cette conversion sont les neurones dopaminergiques (DA) dans la substantia nigra, c’est-à-dire ceux qui deviennent non fonctionnels dans la maladie de Parkinson. En appliquant cette approche, les scientifiques ont démontré la conversion progressive des astrocytes en nouveaux neurones capables d’innerver et repeupler les circuits neuronaux de la la substantia nigra. Ces neurones dopaminergiques induits par l’épuisement du PTB rétablissent puissamment la dopamine striatale, reconstituent le circuit nigrostriatal et inversent les phénotypes moteurs de type maladie de Parkinson.

Chez les souris traitées, un sous-ensemble d’environ 30% des astrocytes, se sont convertis en neurones, augmentant ainsi le nombre total de neurones. Les niveaux de dopamine ont été restaurés à un niveau comparable à celui des souris normales. De plus, les neurones se sont développés et ont envoyé leurs processus dans d’autres parties du cerveau. Il n’y a eu aucun changement chez les souris témoins.

Les souris traitées ont récupérées leur vitalité avec un seul traitement et sont restées complètement indemnes de symptômes de la maladie de Parkinson pour le reste de leur vie. En revanche, les souris témoins n’ont montré aucune amélioration.

Pour expérimenter la conversion des astrocytes du mésencéphale en neurones dopaminergiques, les scientifiques ont utilisé un modèle de la maladie de Parkinson chimiquement induit chez la souris. Le modèle utilisé par l’équipe ne résume pas parfaitement toutes les caractéristiques essentielles de la maladie de Parkinson. À l’avenir, les scientifiques utiliseront un modèle génétique animal plus coûteux de Parkinson.

On peut se demander si cette thérapie est transposable à d’autres maladies neurodégénératives. Cependant la maladie de Parkinson est caractérisée par une atteinte dans une région très spécifique du cerveau. Au contraire dans la maladie d’Alzheimer l’atteinte est globale au cerveau et dans le cas de la sclérose latérale amyotrophique les neurones impliqués sont les neurones moteurs mais cela recouvre une zone géographique considérable, qui s’étend largement hors du système immunitaire central.

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Ce livre retrace les principales réalisations de la recherche sur la SLA au cours des 30 dernières années. Il présente les médicaments en cours d’essai clinique ainsi que les recherches en cours sur les futurs traitements susceptibles d’ici quelques années, d’arrêter la maladie et de fournir un traitement complet en une décennie ou deux.