Tag Archives: Parkinson’s

Neuroscientists peered into the brains of patients with Parkinson’s disease and two similar conditions to see how their neural responses changed over time. The study may provide a new tool for testing experimental medications aimed at alleviating symptoms and slowing the rate at which the diseases damage the brain.

Parkinson’s disease is a neurodegenerative disorder that destroys neurons in the brain that are essential for controlling movement. While many medications exist that lessen the consequences of this neuronal loss, none can prevent the destruction of those cells. Clinical trials for Parkinson’s disease have long relied on observing whether a therapy improves patients’ symptoms, but such studies reveal little about how the treatment affects the underlying progressive neurodegeneration. As a result, while there are treatments that improve symptoms, they become less effective as the neurodegeneration advances. The new study could remedy this issue by providing researchers with measurable targets, called biomarkers, to assess whether a drug slows or even stops the progression of the disease in the brain.

The research team used functional magnetic resonance imaging (fMRI) to measure activity in a set of pre-determined brain areas in healthy controls, individuals with Parkinson’s disease, and patients with two forms of “atypical Parkinsonism” – multiple systems atrophy (MSA) and progressive supranuclear palsy (PSP) – that have symptoms similar to those of Parkinson’s disease. The researchers selected the specific brain regions, which are critical for movement and balance, based on the findings of past studies in people with these three conditions. The participants each underwent two scans spaced a year apart, during which they completed a test that gauged their grip strength.

The healthy controls showed no changes in neural activity after a year, whereas the participants with Parkinson’s showed reductions in the response of two brain regions called the putamen and the primary motor cortex. Previous research had shown reduced activity in the primary motor cortex of Parkinson’s patients, but the new study is the first to suggest that this deficit worsens over time. Activity decreased in MSA patients in the primary motor cortex, the supplementary motor area, and the superior cerebellum, while the individuals with PSP showed a decline in the response of these three areas and the putamen.

The researchers now hope to use their newly discovered biomarkers, in addition to one it had previously identified, to test whether an experimental medication known to improve Parkinson’s symptoms also slows the progression of those brain changes.

Paper: “Functional MRI of disease progression in Parkinson disease and atypical parkinsonian syndromes”

Reprinted from materials provided by NIH/NINDS.

Synucleinopathies, a group of neurodegenerative diseases including Parkinson’s disease, are characterized by the pathological deposition of aggregates of the misfolded α-synuclein protein into inclusions throughout the central and peripheral nervous system. Intercellular propagation (from one neuron to the next) of α-synuclein aggregates contributes to the progression of the neuropathology, but little was known about the mechanism by which spread occurs.

In this study, scientists used fluorescence microscopy to demonstrate that pathogenic α-synuclein fibrils travel between neurons in culture, inside lysosomal vesicles through tunneling nanotubes (TNTs), a new mechanism of intercellular communication.

After being transferred via TNTs, α-synuclein fibrils are able to recruit and induce aggregation of the soluble α-synuclein protein in the cytosol of cells receiving the fibrils, thus explaining the propagation of the disease. The scientists propose that cells overloaded with α-synuclein aggregates in lysosomes dispose of this material by hijacking TNT-mediated intercellular trafficking. However, this results in the disease being spread to naive neurons.

This study demonstrates that TNTs play a significant part in the intercellular transfer of α-synuclein fibrils and reveals the specific role of lysosomes in this process. This represents a major breakthrough in understanding the mechanisms underlying the progression of synucleinopathies.

These compelling findings, together with previous reports from the same team, point to the general role of TNTs in the propagation of prion-like proteins in neurodegenerative diseases and identify TNTs as a new therapeutic target to combat the progression of these incurable diseases.

 

Paper: “Tunneling nanotubes spread fibrillar α‐synuclein by intercellular trafficking of lysosomes”

Reprinted from materials provided by Institut Pasteur.

Researchers have identified — and shown that it may be possible to control — the mechanism that leads to the rapid build-up of the disease-causing ‘plaques’ that are characteristic of Alzheimer’s disease.

The ability of biological molecules, such as our DNA, to replicate themselves is the foundation of life. It is a process that usually involves complex cellular machinery. However, certain protein structures manage to replicate without any additional assistance, such as the small, disease-causing protein fibres — fibrils — that are involved in neurodegenerative disorders, including Alzheimer’s and Parkinson’s.

These fibrils, known as amyloids, become intertwined and entangled with each other, causing the so-called ‘plaques’ that are found in the brains of Alzheimer’s patients. Spontaneous formation of the first amyloid fibrils is very slow, and typically takes several decades, which could explain why Alzheimer’s is usually a disease that affects people in their old age. However, once the first fibrils are formed, they begin to replicate and spread much more rapidly by themselves, making the disease extremely challenging to control.

Despite its importance, the fundamental mechanism of how protein fibrils can self-replicate without any additional machinery is not well understood. In a study published in Nature Physics, a team led by researchers from the Department of Chemistry at the University of Cambridge used a powerful combination of computer simulations and laboratory experiments to identify the necessary requirements for the self-replication of protein fibrils.

The researchers found that the seemingly complicated process of fibril self-replication is actually governed by a simple physical mechanism: the build-up of healthy proteins on the surface of existing fibrils.

The researchers used a molecule known as amyloid-beta, which forms the main component of the amyloid plaques found in the brains of Alzheimer’s patients. They found a relationship between the amount of healthy proteins that are deposited onto the existing fibrils, and the rate of the fibril self-replication. In other words, the greater the build-up of proteins on the fibril, the faster it self-replicates.

They also showed, as a proof of principle, that by changing how the healthy proteins interact with the surface of fibrils, it is possible to control the fibril self-replication.

Paper: “Physical determinants of the self-replication of protein fibrils”
Reprinted from materials provided by the University of Cambridge

Ten international JPND working groups recommended for funding

The EU Joint Programme Neurodegenerative Disease Research (JPND) has released the results of a “rapid-action” call to support working groups of leading scientists to bring forward novel approaches that will enhance the use of brain imaging for neurodegenerative disease research.

Ten working groups have been recommended for funding to address the methodological challenges facing different imaging modalities, among them MRI, PET, ultrasound, MEG and EEG, as well as multimodal approaches. The working groups cover a range of neurodegenerative diseases, including Alzheimer’s disease, Parkinson’s disease, Frontotemporal dementia and Huntington’s disease.

“Brain imaging has made enormous progress in recent years and is currently one of the most promising avenues in neurodegenerative disease research,” said Professor Thomas Gasser, Chair of the JPND Scientific Advisory Board. “If we can solve the challenges in the field, brain imaging could rapidly lead to faster and better diagnoses as well as a deeper understanding of the fundamental aspects and mechanisms of neurodegeneration.”

Although imaging techniques have brought about a dramatic improvement in the understanding of neurodegenerative diseases, there remain a number of significant challenges in the field. These include the execution of multi-centre clinical trials of an unprecedented scale, data transfer across imaging centres and the use of imaging for diagnostics and for measuring clinical outcomes.

To address these questions, on January 8, 2016, JPND launched a call for community-led working groups on harmonisation and alignment in brain imaging methods. The proposals recommended for funding are for top scientists to come together and propose, through ‘best practice’ guidelines and/or methodological frameworks, how to overcome key barriers to the use of imaging in neurodegenerative disease research.

The call attracted proposals with partners from across Europe and beyond, including Asia, Australia, North America and South America. A notable number of groups based in the United States were involved in responses to the call. Funding decisions were based upon scientific evaluation and recommendations to sponsor countries by a JPND peer review panel.

“This call perfectly embodies JPND’s mission and objectives,” said Professor Philippe Amouyel, Chair of the JPND Management Board. “The purpose of JPND is to strengthen coordination and collaboration in neurodegenerative disease research across different countries. We want to ensure that research efforts are not duplicated, to build consensus and to accelerate a path toward a cure that works. This call convenes groups of leading experts to hammer out the hard questions, including the challenges of interoperability and shared and open data, to allow researchers to more rapidly and more fully exploit imaging techniques going forward.”

Each working group is expected to run for a maximum of 9 months. The outputs of the working groups are to be produced by the end of the funding period, and will be published on the JPND website and used for further JPND actions. In addition, a common workshop will be organised to bring together and present the recommendations of each working group, encouraging the further exchange of ideas and wider dissemination to different stakeholder groups.

For more information on the working groups recommended for funding, click here.

npj Parkinson's Disease“Creation of a library of induced pluripotent stem cells from Parkinsonian patients” has been published in npj Parkinson’s Disease. This research was supported in part by JPND through the MADGIC project, selected under the 2015 JPco-fuND call.

FrontiersAgingNeuroscience“Aiming for Study Comparability in Parkinson’s Disease: Proposal for a Modular Set of Biomarker Assessments to be Used in Longitudinal Studies” has been published in Frontiers in Aging Neuroscience. This research was supported by JPND through the BioLoC-PD working group, selected under the  2014 call for working groups to inform cohort studies in neurodegenerative disease research.

NeuronUnderstanding Dopaminergic Cell Death Pathways in Parkinson Disease” has been published in Neuron. This research was supported in part by JPND through the CrossSeeds project, selected in the 2013 call for research projects for cross-disease analysis of pathways related to neurodegenerative diseases, and the SYNaction project, selected under the 2015 JPco-fuND call.

“Conversion of Synthetic Aβ to In Vivo Active Seeds and Amyloid Plaque Formation in a Hippocampal Slice Culture Model” has been published in The Journal of Neuroscience. This research was supported in part by JPND through the NeuTARGETs project, which was selected for support in the 2013 call for research projects for cross-disease analysis of pathways related to neurodegenerative diseases.