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Research Article
Pathological α-synuclein transmission initiated by binding lymphocyte-activation gene 3

Present address: Department of Anatomy and Physiology, Kansas State University, Manhattan, KS 66506, USA.

Present address: State Key Laboratory of Medical Molecular Biology, Department of Immunology, Institute of Basic Medical Sciences, Chinese Academy of Medical Sciences and School of Basic Medicine, Peking Union Medical College, Beijing 100005, China.

Present address: Department of Pharmacology and Toxicology, University of Alabama at Birmingham, Birmingham, AL 35294, USA.

Present address: Institute of Medical Biochemistry Leopoldo de Meis, Federal University of Rio de Janeiro, Rio de Janeiro, RJ, Brazil.

See all Hide authors and affiliations

30 Sep 2016: Vol. 353, Issue 6307, aah3374 DOI: 10.1126/science.aah3374
Xiaobo Mao
Neuroregeneration and Stem Cell Programs, Institute for Cell Engineering, Johns Hopkins University School of Medicine, Baltimore, MD 21205, USA. Department of Neurology, Johns Hopkins University School of Medicine, Baltimore, MD 21205, USA. Adrienne Helis Malvin Medical Research Foundation, New Orleans, LA 70130-2685, USA.
Michael Tianhao Ou
Neuroregeneration and Stem Cell Programs, Institute for Cell Engineering, Johns Hopkins University School of Medicine, Baltimore, MD 21205, USA. Department of Neurology, Johns Hopkins University School of Medicine, Baltimore, MD 21205, USA.
Senthilkumar S. Karuppagounder
Neuroregeneration and Stem Cell Programs, Institute for Cell Engineering, Johns Hopkins University School of Medicine, Baltimore, MD 21205, USA. Department of Neurology, Johns Hopkins University School of Medicine, Baltimore, MD 21205, USA. Adrienne Helis Malvin Medical Research Foundation, New Orleans, LA 70130-2685, USA.
Tae-In Kam
Neuroregeneration and Stem Cell Programs, Institute for Cell Engineering, Johns Hopkins University School of Medicine, Baltimore, MD 21205, USA. Department of Neurology, Johns Hopkins University School of Medicine, Baltimore, MD 21205, USA. Adrienne Helis Malvin Medical Research Foundation, New Orleans, LA 70130-2685, USA.
Xiling Yin
Neuroregeneration and Stem Cell Programs, Institute for Cell Engineering, Johns Hopkins University School of Medicine, Baltimore, MD 21205, USA. Department of Neurology, Johns Hopkins University School of Medicine, Baltimore, MD 21205, USA. Adrienne Helis Malvin Medical Research Foundation, New Orleans, LA 70130-2685, USA.
Yulan Xiong
Neuroregeneration and Stem Cell Programs, Institute for Cell Engineering, Johns Hopkins University School of Medicine, Baltimore, MD 21205, USA. Department of Neurology, Johns Hopkins University School of Medicine, Baltimore, MD 21205, USA. Adrienne Helis Malvin Medical Research Foundation, New Orleans, LA 70130-2685, USA.
Preston Ge
Neuroregeneration and Stem Cell Programs, Institute for Cell Engineering, Johns Hopkins University School of Medicine, Baltimore, MD 21205, USA. Department of Neurology, Johns Hopkins University School of Medicine, Baltimore, MD 21205, USA.
George Essien Umanah
Neuroregeneration and Stem Cell Programs, Institute for Cell Engineering, Johns Hopkins University School of Medicine, Baltimore, MD 21205, USA. Department of Neurology, Johns Hopkins University School of Medicine, Baltimore, MD 21205, USA. Adrienne Helis Malvin Medical Research Foundation, New Orleans, LA 70130-2685, USA.
Saurav Brahmachari
Neuroregeneration and Stem Cell Programs, Institute for Cell Engineering, Johns Hopkins University School of Medicine, Baltimore, MD 21205, USA. Department of Neurology, Johns Hopkins University School of Medicine, Baltimore, MD 21205, USA. Adrienne Helis Malvin Medical Research Foundation, New Orleans, LA 70130-2685, USA.
Joo-Ho Shin
Neuroregeneration and Stem Cell Programs, Institute for Cell Engineering, Johns Hopkins University School of Medicine, Baltimore, MD 21205, USA. Department of Neurology, Johns Hopkins University School of Medicine, Baltimore, MD 21205, USA. Division of Pharmacology, Department of Molecular Cell Biology, Sungkyunkwan University School of Medicine, Samsung Biomedical Research Institute, Suwon 440-746, South Korea.
Ho Chul Kang
Neuroregeneration and Stem Cell Programs, Institute for Cell Engineering, Johns Hopkins University School of Medicine, Baltimore, MD 21205, USA. Department of Neurology, Johns Hopkins University School of Medicine, Baltimore, MD 21205, USA. Department of Physiology, Ajou University School of Medicine, Suwon 443–721, South Korea.
Jianmin Zhang
Neuroregeneration and Stem Cell Programs, Institute for Cell Engineering, Johns Hopkins University School of Medicine, Baltimore, MD 21205, USA. Department of Neurology, Johns Hopkins University School of Medicine, Baltimore, MD 21205, USA.
Jinchong Xu
Neuroregeneration and Stem Cell Programs, Institute for Cell Engineering, Johns Hopkins University School of Medicine, Baltimore, MD 21205, USA. Department of Neurology, Johns Hopkins University School of Medicine, Baltimore, MD 21205, USA. Adrienne Helis Malvin Medical Research Foundation, New Orleans, LA 70130-2685, USA.
Rong Chen
Neuroregeneration and Stem Cell Programs, Institute for Cell Engineering, Johns Hopkins University School of Medicine, Baltimore, MD 21205, USA. Department of Neurology, Johns Hopkins University School of Medicine, Baltimore, MD 21205, USA. Adrienne Helis Malvin Medical Research Foundation, New Orleans, LA 70130-2685, USA.
Hyejin Park
Neuroregeneration and Stem Cell Programs, Institute for Cell Engineering, Johns Hopkins University School of Medicine, Baltimore, MD 21205, USA. Department of Neurology, Johns Hopkins University School of Medicine, Baltimore, MD 21205, USA. Adrienne Helis Malvin Medical Research Foundation, New Orleans, LA 70130-2685, USA.
Shaida A. Andrabi
Neuroregeneration and Stem Cell Programs, Institute for Cell Engineering, Johns Hopkins University School of Medicine, Baltimore, MD 21205, USA. Department of Neurology, Johns Hopkins University School of Medicine, Baltimore, MD 21205, USA. Adrienne Helis Malvin Medical Research Foundation, New Orleans, LA 70130-2685, USA.
Sung Ung Kang
Neuroregeneration and Stem Cell Programs, Institute for Cell Engineering, Johns Hopkins University School of Medicine, Baltimore, MD 21205, USA. Department of Neurology, Johns Hopkins University School of Medicine, Baltimore, MD 21205, USA. Adrienne Helis Malvin Medical Research Foundation, New Orleans, LA 70130-2685, USA.
Rafaella Araújo Gonçalves
Neuroregeneration and Stem Cell Programs, Institute for Cell Engineering, Johns Hopkins University School of Medicine, Baltimore, MD 21205, USA. Department of Neurology, Johns Hopkins University School of Medicine, Baltimore, MD 21205, USA.
Yu Liang
Neuroregeneration and Stem Cell Programs, Institute for Cell Engineering, Johns Hopkins University School of Medicine, Baltimore, MD 21205, USA. Department of Neurology, Johns Hopkins University School of Medicine, Baltimore, MD 21205, USA.
Shu Zhang
Neuroregeneration and Stem Cell Programs, Institute for Cell Engineering, Johns Hopkins University School of Medicine, Baltimore, MD 21205, USA. Department of Neurology, Johns Hopkins University School of Medicine, Baltimore, MD 21205, USA.
Chen Qi
Neuroregeneration and Stem Cell Programs, Institute for Cell Engineering, Johns Hopkins University School of Medicine, Baltimore, MD 21205, USA. Department of Neurology, Johns Hopkins University School of Medicine, Baltimore, MD 21205, USA. Department of Neurology, Xin Hua Hospital affiliated to Shanghai Jiaotong University School of Medicine, Shanghai 200092, China.
Sharon Lam
Neuroregeneration and Stem Cell Programs, Institute for Cell Engineering, Johns Hopkins University School of Medicine, Baltimore, MD 21205, USA. Department of Neurology, Johns Hopkins University School of Medicine, Baltimore, MD 21205, USA.
James A. Keiler
Neuroregeneration and Stem Cell Programs, Institute for Cell Engineering, Johns Hopkins University School of Medicine, Baltimore, MD 21205, USA. Department of Neurology, Johns Hopkins University School of Medicine, Baltimore, MD 21205, USA.
Joel Tyson
Neuroregeneration and Stem Cell Programs, Institute for Cell Engineering, Johns Hopkins University School of Medicine, Baltimore, MD 21205, USA. Department of Neurology, Johns Hopkins University School of Medicine, Baltimore, MD 21205, USA. Johns Hopkins Institute for NanoBio Technology, Johns Hopkins University, Baltimore, MD 21218, USA.
Donghoon Kim
Neuroregeneration and Stem Cell Programs, Institute for Cell Engineering, Johns Hopkins University School of Medicine, Baltimore, MD 21205, USA. Department of Neurology, Johns Hopkins University School of Medicine, Baltimore, MD 21205, USA.
Nikhil Panicker
Neuroregeneration and Stem Cell Programs, Institute for Cell Engineering, Johns Hopkins University School of Medicine, Baltimore, MD 21205, USA. Department of Neurology, Johns Hopkins University School of Medicine, Baltimore, MD 21205, USA. Adrienne Helis Malvin Medical Research Foundation, New Orleans, LA 70130-2685, USA.
Seung Pil Yun
Neuroregeneration and Stem Cell Programs, Institute for Cell Engineering, Johns Hopkins University School of Medicine, Baltimore, MD 21205, USA. Department of Neurology, Johns Hopkins University School of Medicine, Baltimore, MD 21205, USA. Adrienne Helis Malvin Medical Research Foundation, New Orleans, LA 70130-2685, USA.
Creg J. Workman
Department of Immunology, University of Pittsburgh School of Medicine, Pittsburgh, PA 15261, USA.
Dario A. A. Vignali
Department of Immunology, University of Pittsburgh School of Medicine, Pittsburgh, PA 15261, USA. Tumor Microenvironment Center, University of Pittsburgh Cancer Institute, Pittsburgh, PA 15232, USA.
Valina L. Dawson
Neuroregeneration and Stem Cell Programs, Institute for Cell Engineering, Johns Hopkins University School of Medicine, Baltimore, MD 21205, USA. Department of Neurology, Johns Hopkins University School of Medicine, Baltimore, MD 21205, USA. Adrienne Helis Malvin Medical Research Foundation, New Orleans, LA 70130-2685, USA. Department of Physiology, Johns Hopkins University School of Medicine, Baltimore, MD 21205, USA. Solomon H. Snyder Department of Neuroscience, Johns Hopkins University School of Medicine, Baltimore, MD 21205, USA.
Han Seok Ko
Neuroregeneration and Stem Cell Programs, Institute for Cell Engineering, Johns Hopkins University School of Medicine, Baltimore, MD 21205, USA. Department of Neurology, Johns Hopkins University School of Medicine, Baltimore, MD 21205, USA. Adrienne Helis Malvin Medical Research Foundation, New Orleans, LA 70130-2685, USA.
Ted M. Dawson
Neuroregeneration and Stem Cell Programs, Institute for Cell Engineering, Johns Hopkins University School of Medicine, Baltimore, MD 21205, USA. Department of Neurology, Johns Hopkins University School of Medicine, Baltimore, MD 21205, USA. Johns Hopkins Institute for NanoBio Technology, Johns Hopkins University, Baltimore, MD 21218, USA. Solomon H. Snyder Department of Neuroscience, Johns Hopkins University School of Medicine, Baltimore, MD 21205, USA. Department of Pharmacology and Molecular Sciences, Johns Hopkins University School of Medicine, Baltimore, MD 21205, USA.

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INTRODUCTION

Parkinson’s disease (PD) is the second most common neurodegenerative disorder and leads to slowness of movement, tremor, rigidity, and, in the later stages of PD, cognitive impairment. Pathologically, PD is characterized by the accumulation of α-synuclein in Lewy bodies and neurites. There is degeneration of neurons throughout the nervous system, with the degeneration of dopamine neurons in the substantia nigra pars compacta leading to the major symptoms of PD.

RATIONALE

In the brains of PD patients, pathologic α-synuclein seems to spread from cell to cell via self-amplification, propagation, and transmission in a stereotypical and topographical pattern among neighboring cells and/or anatomically connected brain regions. The spread or transmission of pathologic α-synuclein is emerging as a potentially important driver of PD pathogenesis. The underlying mechanisms and molecular entities responsible for the transmission of pathologic α-synuclein from cell to cell are not known, but the entry of pathologic α-synuclein into neurons is thought to occur, in part, through an active clathrin-dependent endocytic process.

RESULTS

Using recombinant α-synuclein preformed fibrils (PFF) as a model system with which to study the transmission of misfolded α-synuclein from neuron to neuron, we screened a library encoding transmembrane proteins for α-synuclein-biotin PFF–binding candidates via detection with streptavidin-AP (alkaline phosphatase) staining. Three positive clones were identified that bind α-synuclein PFF and include lymphocyte-activation gene 3 (LAG3), neurexin 1β, and amyloid β precursor-like protein 1 (APLP1). Of these three transmembrane proteins, LAG3 demonstrated the highest ratio of selectivity for α-synuclein PFF over the α-synuclein monomer. α-Synuclein PFF bind to LAG3 in a saturable manner (dissociation constant = 77 nM), whereas the α-synuclein monomer does not bind to LAG3. Co-immunoprecipitation also suggests that pathological α-synuclein PFF specifically bind to LAG3. Tau PFF, β-amyloid oligomer, and β-amyloid PFF do not bind to LAG3, indicating that LAG3 is specific for α-synuclein PFF. The internalization of α-synuclein PFF involves LAG3 because deletion of LAG3 reduces the endocytosis of α-synuclein PFF. LAG3 colocalizes with the endosomal guanosine triphosphatases Rab5 and Rab7 and coendocytoses with pathologic α-synuclein. Neuron-to-neuron transmission of pathologic α-synuclein and the accompanying pathology and neurotoxicity is substantially attenuated by deletion of LAG3 or by antibodies to LAG3. The lack of LAG3 also substantially delayed α-synuclein PFF–induced loss of dopamine neurons, as well as biochemical and behavioral deficits in vivo.

We discovered that pathologic α-synuclein transmission and toxicity is initiated by binding to LAG3 and that neuron-to-neuron transmission of pathological α-synuclein involves the endocytosis of exogenous α-synuclein PFF by the engagement of LAG3 on neurons. Depletion of LAG3 or antibodies to LAG3 substantially reduces the pathology set in motion by the transmission of pathologic α-synuclein. The identification of LAG3 as an α-synuclein PFF–binding protein provides a new target for developing therapeutics designed to slow the progression of PD and related α-synucleinopathies.

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28 Jun 2018
Job
Closing date: 27 Jul 2018

Requisition ID: req2212

Job Title: Senior Field Coordinator

Sector: Operations

Employment Category: Fixed Term

Employment Type: Full-Time

Location: Kenya-Kakuma

Job Description

Background:

Kakuma was established in 1992 and is the largest and third oldest camp in Kenya and it host about 192,000 Refugees majority being South Sudanese, followed by Somalis and others. The Camp has more than 10 different nationalities at present. Most refugees and asylum seekers who arrived at Kakuma in the last few years are staying with relatives but some have been settled outside in a new settlement called Kalubeyi some 15 kilomters outside Kakuma.The IRC has implemented refugee assistance projects in Kakuma since 1992 and has been the lead health, and SGBV implementing partner in Kakuma.The IRC provides primary and secondary healthcare services, targeted nutritional services, quality reproductive health, and HIV related services, as well as the protection and empowerment of women and girls.

SCOPE OF WORK:

The IRC seeks an experienced Senior Field Coordinator with significant humanitarian operations experience to manage the IRC's field offices, staff, and operations. The individual must have previous experience working in volatile environments and in Refugee setting . The Field Coordinator will supervise staff, manage the office premises, liaise with local authorities, and contribute to program design and implementation.

Job Purpose/Objective

The Senior Field Coordinator (FC) plays a key role in the overall leadership and management of the IRC Kenya Program. The senior Field Coordinator leads IRCs response in Kakuma Field Site and is responsible for supporting, coordinating and supervising timely and high-quality program implementation, with a specific focus in ensuring the effective functioning of all the support functions of the program. Under the supervision of Deputy Director of Operations (DDO), the senior Field Coordinator will be responsible for the overall field coordination, program support, and field office management working in close collaboration with other members of the senior management team including the Country Director, Deputy Director of Program (DDP), Deputy Director Grants Accountability, Finance Controller, Senior HR Coordinator, Technical Coordinators (Heath, WPE, Nutrition, Monitoring and evaluation Coordinator etc.). The Field Coordinator will be based in Kakuma and may travel to other field sites as and when is required required.

Responsibilities and specific tasks:

Field Office and Program Management

Grants Management and Reporting

Monitoring Evaluation

Strategic Planning

Human Resource Management

Finance and Supply Chain and ICT Management

Security Management

Representation and Coordination

Key Working Relationships:

Position Reports to Deputy Director Operations

The position directly supervises Program Managers; HR lead; Finance Manager and Supply Chain departments in the field site.

Indirect Reporting: None; Direct supervisees have dotted lines to their Program/Technical Coordinators. Other Internal and/or external contacts:

Internal:

External:

Requirements:

Personal Characteristics:

Standards of Professional Conduct: The IRC and IRC workers must adhere to the values and principles outlined in the IRC Way - Code of Conduct. These are Integrity, Service, and Accountability. In accordance with these values, the IRC operates and enforces policies on Beneficiary Protection from Exploitation and Abuse, Child Safeguarding, Harassment-Free Workplace, Fiscal Integrity, Anti-Retaliation, Combating Trafficking in Persons and several others.

Gender Equality: IRC is committed to narrowing the gender gap in leadership positions. We offer benefits that provide an enabling environment for women to participate in our workforce including parental leave, gender-sensitive security protocols and other supportive benefits and allowances.

Country Director, Deputy Director Programs, Program Technical Coordinators (Health Services Co; Partnerships Grants Co; Nutrition Co; WPE Co; ME Co)

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15.07

605 years since the battle of Grunwald

On 15 July 1410, aPolish-Lithuanian army led by King Władysław Jagiełło routed Teutonic Order forces in what was one of Medieval Europe’s biggest battles, fought near the village of Grunwald. The engagement’s re-enactments and knights’ tournaments are organized near the scene of the battle each year.

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"We are grateful for the liberation from the fascist occupation of 1945. But then for the next 45 years the Soviet army dictated who would rule Poland - and it was not aleadership chosen by Poles," says Polish FM in an interview with Kommersant.

Kommersant: Afew weeks ago, television screens around the world broadcast images from Warsaw showing Donald Trump's visit and his first "European speech". At that time, the Polish leadership also announced its intention to purchase several Patriot missile batteries from the United States - in addition to the ten whose delivery began already in 2010. Do you know when and for what delivery the agreement will be signed?

Does the number of batteries depend on the price? Polish media reported that there would be eight of them.

Speaking of additional NATO forces, are you referring to their fixed deployment?

But at the same time, you say, of course, that this additional weapon that Poland would like to deploy at home is only defensive and cannot be used for apreventive strike?

But, for example, the Russian side also talks about the defensive nature of its military operations.

So am Icorrect in understanding that Warsaw's desire to deploy additional Patriot batteries is related to the plans of the Russian side to bolster the missile brigade in Kaliningrad Oblast?

Are you ready to deploy medium and small range missiles at home if the US Congress considers the INF Treaty and wants to send such missiles to Europe?

In these troubled conditions, do the defence ministries of Poland and Russia maintain direct relations with regard to military matters?

Meanwhile, diplomatic relations are maintained: in July, bilateral consultations were held in Moscow with the participation of Undersecretary of State Joanna Wronecka and Deputy Minister Gennady Gatilov in relation with Poland's UN Security Council membership. Does this imply that in the present circumstances this is the only field of cooperation between Poland and Russia?

Have you directly proposed ameeting with the Russian minister?

Returning to the Group for Difficult Matters: Do you know who is currently the co-chairman of the Russian side?

According to one account, which Iheard in Moscow, amajor grievance was the substitution of Adam Rotfeld, an influential and respected former minister, arepresentative of the academic community.

Do you think that some sort of progress can be made on this subject within the framework of the UNSC? To somehow alleviate the differences of opinion?

In another interview you announced that Poland’s priorities also include the Syrian conflict as well as the crises in the Middle East and Ukraine...

Kiev has called for UN peacekeepers to be sent to the Donbas. Would you support this initiative in UNSC debates?

So it is too early to talk about the conflict being frozen?

From both sides?

One of the arguments put forward by supporters of the volunteers in the Donbas is the following: look at what is going on in western Ukraine, look at the rise of Ukrainian nationalist tendencies, do you want them to affect the Russian population in the Donbas?

What about the UPA's heroism? You yourself recently stated that "Ukraine will not enter Europe with Bandera”.

But can one not draw the conclusion from this that your advice does not work? Just look at the change of street names in Ukraine in honour of Bandera and Shukhevych.

So you want to find new heroes?

And what about the Ukrainians?

When you repeated this, were you not upset as aresult of the harsh reaction from the Ukrainians?

As regards support, it seems that Poland's position is the most principled in the EU. Is this really the case?

In what sense?

But if the numbers are growing and the conflict is freezing, then perhaps the problem does not lie in the conflict?

Do you think this is aconvincing excuse for not reforming?

But this also does not work? We talked to you before you were appointed foreign minister MFA in 2015 and you said then that the reforms are ongoing but are slow due to military spending. It appears that in fact no European can influence Kiev?

In your opinion, did at least some reform succeed?

This is not the main topic of our talk, but Ihave to ask: my cousin’s grandfather was killed during an uprising in aGerman concentration camp in the north of Poland and buried there. My grandfather on the other hand was injured in Poland and miraculously survived - in the family they say that aPolish woman saved him. Do you really think it is so important to destroy this common history by demolishing the monuments of the Red Army in Poland?

Are you convinced that such symbolism will be destroyed rather than monuments of soldiers?

Have you discussed with your Russian counterparts the threat of the Russian Federation's Foreign Ministry about the introduction of "asymmetric actions" should the demolition of the monuments proceed?

In September, the European Commission intends to discuss with the EU states the final parameters of the mandate for talks with the Russian Federation on the legal status of Nord Stream 2. The Polish leadership has repeatedly stated that they are opposed to this project. What do you think is the meaning of similar talks, taking into account the extreme positions of supporters and opponents of the project?

But this is business: the Germans have the opportunity to buy gas elsewhere, and you do not.

Meanwhile, Germany and Austria have already threatened to retaliate if their companies are affected by US sanctions. And won’t you have to choose between the US and European partners if the issue comes to the stage of discussing retaliatory actions in the European Union?

Is Poland planning to extend the contract for the transit of Russian gas to Germany through the Yamal-Europe gas pipeline, which ends on January 1, 2020?

But the talks on extending the contract have not even started yet, even though Gazprom sent the query over ayear ago.

But if you had alot of gas, would you not have tried to sell it so as not to pay for transit and free yourself from political risks?

It appears that you do not see the chance for the warming [of relations]?

Does it not seem to you that the criticism you direct at Russia is similar to the way some European politicians criticize Poland? What else does Warsaw need - and you do not even want to take in refugees?

But you know that Warsaw is being criticized anyway for the position on migration as well as for controversial legislation. Maybe Russia and Poland are similar in terms of "privileged conditions"?

Source: Kommersant

Witold Waszczykowski, Polish Foreign Minister: For now it is not known. We signed apreliminary agreement and expressed our expectations regarding the specification of these batteries, radars and other accompanying equipment. We are now waiting for the US response regarding technical details and pricing. We do not expect the delivery to arrive tomorrow.

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