帕金森病（Parkinson's disease）是一种主要的神经退行性疾病。 它目前缺乏可以直接针对致病过程的临床相关治疗方法。 目前的临床方法，如深部脑刺激和左旋多巴和多巴胺激动剂的药物治疗，只能缓解症状。 这些治疗的功效在很大程度上受到其不良并发症和副作用的限制。 资料来源：Ajpolino 通过维基百科

由于 α-突触核蛋白在帕金森病的某些病理条件下过度表达，而这些上调的蛋白质会干扰许多生理过程，如内质网到高尔基体的转运、突触传递和线粒体功能和形态，有力地击倒过度表达的 α-突触核蛋白可能 与简单地抑制有毒 α-突触核蛋白寡聚体的形成相比，在恢复帕金森病大脑中的正常细胞功能方面具有更好的神经保护功效。

使用反义寡核苷酸和小干扰 RNA (siRNA) 等遗传操作敲除 α-突触核蛋白，已在各种帕金森病模型中显示出对多巴胺能神经元的保护作用。

然而，将这些操作转化为有效的帕金森病疗法的临床转化成本高昂且不舒服，因为它主要是通过侵入性注射或病毒感染来完成的。 这些技术在临床上可能不适用于人类患者的治疗用途。

在这里，科学家们报告了一种短的、血脑屏障和质膜渗透性合成肽的开发，该肽可以通过蛋白酶体降解快速减少内源性 α-突触核蛋白。

科学家们使用帕金森病的体外和体内模型，为使用这种小的 α-突触核蛋白敲低肽作为潜在的帕金森病治疗提供了原理证明。

作者首先证明了 Tat-βsyn-degron 肽可以在体外和体内特异性地降低 α-突触核蛋白的水平。 作者随后表明，肽诱导的 α-突触核蛋白敲低与保护多巴胺能神经元免受帕金森病培养模型中毒素诱导的损伤有关。

最重要的是，科学家们能够在两个充分表征的帕金森病动物模型中证明全身应用 Tat-βsyn-degron 肽作为有效的帕金森病治疗方法的治疗潜力。

他们的 α-突触核蛋白敲低肽 (Tat-βsyn-degron) 具有创新性，因为该肽直接针对致病过程之一，有望阻止或减缓疾病的进展。

此外，肽介导的敲低比反义或 siRNA 介导的敲低具有明显的时间优势。 α-突触核蛋白是一种非常稳定的蛋白质，具有很长的半衰期，而通过劫持细胞中的内源性蛋白酶体降解系统，Tat-βsyn-degron 肽在几个小时内产生了 α-突触核蛋白的快速而稳健的降解。

有趣的是，α-突触核蛋白也在中枢神经系统以外的组织中表达，科学家发现单次腹膜内注射 Tat-βsyn-degron 肽同样降低了肾脏和脾脏中的 α-突触核蛋白表达 野生型 C57BL/6 小鼠。

最近在 3 期临床试验中取得的成功已经证明，Tat 融合短肽不仅安全，而且在保护神经元免受人体缺血性损伤方面具有治疗效果。作者希望这种 α-突触核蛋白敲低肽也有可能被迅速转化为临床，作为一种直接针对帕金森病致病过程的有效改善疾病的治疗方法。

由于他们的肽介导的蛋白质敲低方法的多功能性，科学家们理论上可以通过简单地改变靶向肽的蛋白质结合序列来靶向引起疾病的细胞蛋白质。由于许多人类疾病，包括一些与年龄相关的神经退行性疾病，如 ALS、阿尔茨海默氏病和亨廷顿氏病，在病理上是由蛋白质由于其突变和/或表达水平增加而获得功能引起的，拟议的研究有望促进帕金森病以外的人类疾病新疗法的开发。

Parkinson's disease is a progressive neurodegenerative disease with no cure and few treatment options.

Photobiomodulation has been used successfully in animal models. A new medRxiv preprint describes a proof-of-concept clinical study to assess the efficacy of photobiomodulation in Parkinson's disease, in order to inform on treatment regimens and outcome measures for a future randomized, placebo-controlled study.

Photobiomodulation therapy is the use of narrow wavelength bands of non-thermal light to modulate cellular responses. The main target of photobiomodulation is probably the cytochrome-C-oxidase, which absorbs red and near infrared light. Photobiomodulation therapy has a good safety profile.

The photobiomodulation was administered transcranially with a VieLight Gamma device (4 LEDs, 240 joules), intranasally with a VieLight Gamma nasal device (1 LED, 15 joules), transdermally to the C1/C2 region of the neck and to the abdomen with an Irradia MID 2.5 laser device (4 laser diodes, 39.6 joules) or a MIDCARE laser device (2 diodes 39.6 joules).

All participants received the same dose of total energy from the photobiomodulation treatment throughout the study. The treatment protocol made it possible to not to use safety glasses. Participants' adherence to the treatment protocol was monitored by caregivers and reported during the final assessment.

The primary outcome measure was improvement timed up and go (TUG) as a measure of mobility. Secondary outcome measures were mobility, cognition, fine motor skill, micrographia and static balance. Quality of life outcome measures and patient-reported symptomatic changes, including depression, are reported separately.

Twelve participants with idiopathic Parkinson's disease were recruited. Six were randomly selected to start 12 weeks of transcranial, intranasal, cervical and abdominal photobiomodulation. The other 6 were put on a waiting list for 14 weeks before starting treatment. After the 12 week treatment period, all participants received photobiomodulation devices to continue treatment at home.

Participants were assessed for mobility, fine motor skills, balance, and cognition before the start of treatment, after 4 weeks of treatment, after 12 weeks of treatment and the end of the home treatment period.

Measures of mobility, cognition, dynamic balance and fine motor skills were significantly improved (p <0.05) with photobiomodulation treatment for 12 weeks and up to one year. Individual improvements varied, but many continued for up to a year with sustained home treatment. Improvements were maintained as long as treatment continued, up to a year in neurodegenerative disease where a decline is generally expected. No side effects of the treatment were observed.

The current study did not have a placebo arm to quantify the placebo effect, but the related Hawthorne effect was assessed. The Hawthorne effect occurs in response to participation in research. It happens when a patient is observed during a study and has been recognized as a confounding factor in the results of clinical trials in Parkinson's disease, for example depending on whether an evaluation is done openly or secretly.

In the present study, participants on the waiting list (group B) showed an improvement in outcome measures before the start of treatment, with some of these improvements being sufficient to qualify as IMID, thus demonstrating a measurable Hawthorne effect. The other possibility is that the participants improved due to a practice effect with repeated assessments.

In conclusion, photobiomodulation has been shown to be a safe and potentially effective treatment for a range of clinical signs and symptoms of Parkinson's disease. Home treatment for Parkinson's disease on its own or with the help of a caregiver can be an effective treatment option. The results of this study indicate that a large double-blind clinical trial of the application of this technology to Parkinson's disease is warranted.

TRIAL REGISTRATION: Australian New Zealand Clinical Trials Registry, registration. number: ACTRN12618000038291p, registered on 12/01/2018

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This book retraces the main achievements of ALS research over the last 30 years, presents the drugs under clinical trial, as well as ongoing research on future treatments likely to be able stop the disease in a few years and to provide a complete cure in a decade or two.

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