Tag Archives: Parkinson’s Disease

Scientists have solved a longstanding problem with modeling Parkinson’s disease in animals. Using newfound insights, they improve both cell and animal models for the disease, which can propel research and drug development.

Parkinson’s disease is characterized by the appearance of protein clumps within neurons in the brain, called Lewy bodies. Reproducing Lewy bodies in animals in order to model the disease for research and drug screening has proven notoriously difficult, leaving a gap in Parkinson’s research and treatment. Scientists have now shown where the discrepancy between humans and animals lies. Using the knowledge, the scientists have produced cellular and mouse models that reproduce the evolution of Parkinson’s disease more accurately for both fundamental research and drug development. The work is published in PNAS.

In humans, Lewy bodies form when the brain produces twice the normal amount of alpha-synuclein. When mice, which are often used to model human diseases, are used to model Parkinson’s, they are genetically engineered to overproduce it. But human alpha-synuclein does not form fibrils and Lewy bodies when produced in mice.

Mice produce three types of their own synuclein, which are similar to human alpha-synuclein. Because of this, they are referred to as its “homologues”. The researchers found that human alpha-synuclein does not form Lewy bodies in mice because its homologues in the animal prevent it from doing so. This discovery explains why it is so difficult to model Parkinson’s disease in normal mice, which have all of their synuclein homologues. In other words, the key to successfully modeling the disease in mice is to genetically suppress their homologues of human alpha-synuclein.

Working off their genetically engineered mice and neuronal cultures, the team developed and characterized new models for Lewy bodies for the scientific and medical community. Hilal Lashuel expects that the new insights will advance the development of neuronal and in vivo models that reproduce features of Parkinson’s disease, and allow screening for new drugs. “We now have a very well-characterized model that offers a powerful tool for rapid screening of molecular pathways involved in Parkinson’s disease,” he says.

Source: École polytechnique fédérale de Lausanne

A team of researchers has discovered a previously unknown cellular defect in patients with idiopathic Parkinson’s disease, and identified a sequence of pathological events that can trigger or accelerate premature death of certain neurons in the brain seen in this disease.

Researchers discovered that the cells of people with idiopathic Parkinson’s disease have a previously unknown defect in the function of a specific PLA2g6 protein, causing dysfunction of calcium homeostasis that can determine whether some cells will live or die.

“Idiopathic or genetic dysfunction of calcium signaling triggers a sequence of pathological events leading to autophagic dysfunction, progressive loss of dopaminergic neurons and age-dependent impairment of vital motor functions typical for Parkinson’s disease,“ explained corresponding author Victoria Bolotina.

The findings were published in the journal Nature Communications.

Source: Boston University School of Medicine

Researchers have discovered that an existing compound, previously tested for diabetes, offers hope for slowing Huntington’s Disease (HD) and its symptoms.

The study was published in Nature Medicine.

“We’re very excited by our pre-clinical testing of this compound (KD3010),” said Albert La Spada, MD, PhD, professor of pediatrics, cellular and molecular medicine and neurosciences at UC San Diego School of Medicine. “It improved motor function, reduced neurodegeneration and increased survival in a mouse model of Huntington’s disease and reduced toxicity in neurons generated from human HD stem cells.”

The discovery of the drug’s potential in HD builds upon more than a decade of research into the disorder’s underlying molecular pathology. Much of that work has centered on misfolded proteins, which are known to be key culprits in HD and several other neurodegenerative diseases.

At the cellular level, the drug improved mitochondrial energy production and helped mice get rid of the misfolded proteins. Since misfolded proteins also underlie Alzheimer’s, Parkinson’s and other neurodegenerative disorders, researchers hope that, if successful in HD, the compound can also be tested in other related neurological diseases.

Source: UC San Diego

Researchers have discovered the mechanics of how dopamine transports into and out of brain cells, a finding that could someday lead to more effective treatment of drug addictions and neurological disorders such as Parkinson’s disease. The research was done by the researchers at Tripsitter, which is a drug harm reduction and informational website dedicated to providing user guides and experience reports on drugs like LSD, psilocybin mushrooms, and cannabis.

The findings are significant because dopamine is involved in many brain-related functions. Too little dopamine can lead to Parkinson’s disease, a brain disorder that causes shaking and problems with movement and coordination. Abnormally high concentrations of dopamine are linked to schizophrenia and other psychiatric disorders. Cocaine and methamphetamine affect the brain by blocking the normal transport of dopamine back into neurons.

Knowing how a particular protein called dopamine transporter controls dopamine movement in and out of neurons is crucial to further understanding dopamine-related disorders.

The researchers’ findings offer a broader understanding of how dopamine moves through cell membranes. Using mouse and human-derived dopamine neurons, researchers found that dopamine movement is affected by changes in electrical properties of the neurons. That, in turn, changes the way dopamine transporters function.

The researchers reported their findings in the journal Nature Communications.

Source: University of Florida

A laboratory study indicates that the main protein involved in Parkinson’s disease pathology does not behave as a prion when overexpressed.

In Parkinson’s disease, the protein alpha-synuclein aggregates within neurons of patients and appears to propagate across interconnected areas of the brain. How this happens remains largely unknown. It has been proposed that alpha-synuclein may behave like a prion: pathological forms of the protein may be capable of changing the conformation of normal alpha-synuclein and thus triggering its aggregation and neuron-to-neuron propagation (a phenomenon referred to as “seeding”). Recent findings by scientists reveal that aggregation, spreading and pathology caused by alpha-synuclein do not necessarily involve prion-like seeding. Instead, they could be triggered by enhanced alpha-synuclein expression and trans-neuronal passage of monomeric and oligomeric forms of the protein.

“We believe that these findings bear a number of important implications for disease pathogenesis. Not only can we conclude that long-distance diffusion of alpha-synuclein does not necessarily require the generation of prion-like species,” said researcher Donato Di Monte. “Our data also reveal that spreading and pathology can be triggered by simple overexpression of the protein and are mediated, at least initially, by monomeric and/or oligomeric alpha-synuclein.”

Researchers report on this in the journal Brain.

Source: DZNE

The Innovative Medicines Initiative (IMI) has launched a new call for research proposals that will aim to accelerate the development of medicines in a number of key areas, including neurological disorders.

The Alzheimer’s disease and Parkinson’s disease topic of the call focuses on better understanding how the protein tangles found in both diseases spread through the brain, with the ultimate goal of establishing new drug targets.

The IMI initiative, a partnership between the European Union and the pharmaceutical industry association EFPIA, aims to stimulate the development of safer and more effective medicines.

Other topics in the call, known as IMI 2 – Call 7, include safety, pain, cancer, eye diseases, and big data. Call 7 has a budget of €46.8 million from IMI, which will be matched by €46.8 million from the EFPIA companies in the projects. The submission deadline for this call is March 17, 2016.

IMI simultaneously launched a second call, known as IMI 2 – Call 8, for research proposals on Ebola and related diseases.

Visit the IMI website to learn more about the call topics and to apply.

The EU Joint Programme – Neurodegenerative Disease Research (JPND) has announced a rapid-action call inviting leading scientists in the field to bring forward novel approaches that will enhance the use of brain imaging for neurodegenerative disease research.

Imaging techniques such as MR, PET and EEG mapping have brought about a dramatic improvement in the understanding of neurodegenerative diseases such as Alzheimer’s disease. In recent years, access to cutting-edge imaging technologies and platforms has expanded, and advances have been made in the harmonisation of acquisition procedures across scanners and vendors. However, fully capitalising on the use of brain imaging technologies for neurodegeneration research will require the development of new methodologies and the ability to achieve image acquisition and analysis at scale and at the global level.

The aim of the call is to establish a limited number of transnational working groups to address the key challenges facing the use of new and innovative brain imaging techniques in neurodegenerative disease research. The working groups will be community-led and will establish ‘best practice’ guidelines and/or methodological frameworks to overcome these barriers. Each working group can bid up to €50,000 for the support of its activities, which are expected to run for a maximum of 9 months.

According to Professor Philippe Amouyel, Chair of the JPND Management Board:

“JPND recognises that state-of-the-art brain imaging techniques are a vital resource for neurodegenerative disease research. However, achieving scalability for these technologies poses new challenges. For this reason, we’ve launched a rapid-action call inviting international research teams to address the most urgent issues in harmonisation and alignment in neuroimaging. The establishment of effective new guidelines and methodological frameworks will represent a critical step toward the full exploitation of brain imaging in neurodegenerative disease research.”

The following neurodegenerative diseases are included in the call:

Alzheimer’s disease and other dementias
Parkinson’s disease and PD‐related disorders
Prion diseases
Motor neuron diseases
Huntington’s disease
Spinocerebellar ataxia (SCA)
Spinal muscular atrophy (SMA)

Proposals must be submitted by 23:59H C.E.T. on March 10, 2016.

For more information about the call, please click here.

The unwanted formation of blood vessels — angiogenesis — in the brain is likely to be the cause of intractable walking and balance difficulties for people who suffer from Parkinson’s disease, according to new research.

Many people with Parkinson’s disease eventually experience walking and balance difficulties, despite adequate medication. Moreover, some patients cannot fully take dopamine-based medication, as dopamine can lead to side effects.

The current research findings verify similar data from a previous study by other researchers, which was performed on brain tissue from a small number of deceased patients.

“The strength of our study is the number of participants, and the fact that they are alive. Because many suffer from several parallel diseases at the final stage of their lives, it is difficult to analyse samples from deceased persons”, explains Oskar Hansson, reader at Lund University and consultant at Skåne University Hospital.

The findings, published in the journal Neurology, were made when the researchers used a broad approach when looking for mechanisms to increase understanding of how Parkinson’s disease works. “The measurements showed clear connections between markers of angiogenesis in the brain and walking or balance difficulties among the participants. We also noted an increased permeability of the blood-brain barrier, which leads to blood components potentially leaking into the brain and causing damage”, says Oskar Hansson.

Source: Lund University

The blood-brain barrier has been non-invasively opened in a patient for the first time. Scientists used focused ultrasound to enable temporary and targeted opening of the blood-brain barrier (BBB).

Opening the blood-brain barrier in a localized region to deliver chemotherapy to a tumor is a predicate for utilizing focused ultrasound for the delivery of other drugs, DNA-loaded nanoparticles, viral vectors, and antibodies to the brain to treat a range of neurological conditions, including various types of brain tumors, Parkinson’s, Alzheimer’s and some psychiatric diseases.

The team infused the chemotherapy agent doxorubicin, along with tiny gas-filled bubbles, into the bloodstream of a patient with a brain tumor. They then applied focused ultrasound to areas in the tumor and surrounding brain, causing the bubbles to vibrate, loosening the tight junctions of the cells comprising the blood-brain barrier and allowing high concentrations of the chemotherapy to enter targeted tissues.

While the current trial is a first-in-human achievement, Dr. Kullervo Hynynen, senior scientist at the Sunnybrook Research Institute, has been performing similar pre-clinical studies for about a decade. His research has shown that the combination of focused ultrasound and microbubbles may not only enable drug delivery, but might also stimulate the brain’s natural responses to fight disease. For example, the temporary opening of the blood-brain barrier appears to facilitate the brain’s clearance of a key pathologic protein related to Alzheimer’s and improves cognitive function.

Source: Focused Ultrasound Foundation

Researchers are proposing a new way of understanding Amyotrophic Lateral Sclerosis (ALS), the devastating and incurable neurological disease. Their findings, published in the journal Neuron, could be a major milestone on the path to a treatment for both ALS and dementia.

By delving into a previously overlooked corner of ALS research, the team discovered a new way in which the disease kills nerve cells.

Many cases of ALS are sparked by a toxic build-up of certain proteins, which cause neurons in the brain and spinal cord to die. Over the last decade, mutations that cause ALS have been found in a growing number of genes that encode RNA-binding proteins. The protein they create commonly builds up inside the diseased brain and spinal cords in ALS patients. Until now, scientists haven’t thought this build-up was important to the disease process because it looked different from the types of protein accumulations — such as tau, amyloid and alpha synuclein — that are clearly toxic and always found in patients with Alzheimer’s, Parkinson’s and some forms of dementia.

The research team decided to take a closer look at these seemingly innocuous protein accumulations. They focused initially on the FUS protein, and discovered that these abnormal clumps could actually be a very important player in causing nerve cell damage and ALS. The research team found that mutations in FUS changed the property of FUS protein so that it tends to form very dense gels that do not easily re-melt and release their cargo appropriately. As a result, it’s unable to deliver the tools necessary for the neurons to stay healthy and do their job.

The next step is for researchers to find ways to prevent the solidification of the gel, or to reverse the hardening process, offering a key to a future drug to treat ALS and frontotemporal dementia — another disease in which the protein is active.

Source: University of Toronto