Breaking News
November 16, 2018 - Drug used to treat dizziness may slow down growth of triple-negative breast cancer
November 16, 2018 - AHA: Icosapent Ethyl Cuts CV Risk From Elevated Triglycerides
November 16, 2018 - ‘Orphan’ RNAs make cancer deadlier, but potentially easier to diagnose
November 16, 2018 - Air Cube touches down at hospital | News Center
November 16, 2018 - CRISPR-based tool shown to enhance cell-based immunotherapy
November 16, 2018 - Mechanisms that govern HIV latency differ in the gut and blood, finds study
November 16, 2018 - Researchers unravel mystery of NPM1 protein in acute myeloid leukemia
November 16, 2018 - High school students less likely to select milk, fruit for lunch when fruit juice is available
November 16, 2018 - Football coaches with great emotional competence are more successful
November 16, 2018 - Researchers awarded $10 million grant to address root causes of asthma in Puerto Rico
November 16, 2018 - Health Tip: Manage Morning Sickness
November 16, 2018 - Immunotherapy combination and chemotherapy show encouraging results in Phase II acute myeloid leukemia study
November 16, 2018 - ACC Latin America Conference brings experts to discuss latest cardiovascular science
November 16, 2018 - Pooled analysis of Intersect ENT’s steroid releasing implants in patients after frontal sinus surgery to be published
November 16, 2018 - Expectations about pain intensity can become self-fulfilling prophecies
November 16, 2018 - NIH awards $3.4 million to UC researchers to study gastrointestinal lymphatic system
November 16, 2018 - Scientist Dr David Taylor of MR Solutions is a finalist in the BMW i UK Tech Founder Awards
November 16, 2018 - Earlier treatment could help reverse autistic-like behavior in tuberous sclerosis
November 16, 2018 - Vegetables and salad may include bacteria that are resistant to antibiotics
November 16, 2018 - Autism linked to prolonged connection between brain regions
November 16, 2018 - Endocrine Society chooses four Diabetes Caucus leaders as winners of Diabetes Champion Award
November 16, 2018 - Brain and muscle cells found within kidney organoids
November 16, 2018 - Person’s sex hormones may play key role in trauma survival, finds study
November 16, 2018 - PTEN Genetic Test: MedlinePlus Lab Test Information
November 16, 2018 - Toxic metal pollution linked with development of autism spectrum disorder
November 16, 2018 - Calcified nodules in the retina increase risk for progression to late stages of AMD
November 16, 2018 - ZEISS teams up with arivis AG to offer complete 3D imaging solutions
November 16, 2018 - Georgia State professor receives $1.2 million grant to study how the brain controls eating behavior
November 16, 2018 - Specific bacterial toxins reduce number of cells suppressing immune response
November 16, 2018 - Review by ID physician improves outcomes for outpatient parenteral antimicrobial therapy
November 16, 2018 - Conditions that produce signs similar to arthritis
November 16, 2018 - New artificial intelligence-based method predicts treatment effectiveness
November 16, 2018 - AHA: Dapagliflozin Noninferior to Placebo for MACE in T2DM
November 16, 2018 - Surgery remains best treatment for appendicitis, Stanford study finds
November 16, 2018 - Non-surgical fistula creation system Ellipsys becomes key focus of attention at CiDA
November 16, 2018 - Researchers find no link between ‘allergy friendly’ dogs and lower risk of asthma
November 16, 2018 - Researchers elucidate new rules of connectivity of neurons in the neocortex
November 16, 2018 - Treating children with ‘bubble baby disease’
November 16, 2018 - Nexus announces availability of Arsenic Trioxide Injection in the US
November 16, 2018 - Researchers find metabolite shuttle between cells in the liver that may combat tissue fibrosis
November 16, 2018 - AHA: PTSD Common Among Those Who Suffer Tear in the Aorta’s Wall
November 16, 2018 - Many RA patients’ pain related to central nervous system
November 16, 2018 - Changes in Himalayan gut microbiomes linked to diet
November 16, 2018 - Inhibition of prostaglandin E2 enhances ability to combat infectious colitis
November 16, 2018 - Chronic dry eye can slow reading rate and disrupt day to day tasks
November 16, 2018 - Researchers develop new drug molecule that inhibits inflammation
November 16, 2018 - Dementia symptoms peak in winter and spring, study finds
November 16, 2018 - Stanford tobacco researcher weighs in on JUUL
November 16, 2018 - Increasing omega-3 fatty acid intake during pregnancy reduces risk of premature birth, review finds
November 16, 2018 - Researchers find no link between infants waking up at night and later developmental problems
November 16, 2018 - Both parents and children agree about confidential medical services
November 16, 2018 - FDA warns against use of unapproved pain medications with implanted pumps
November 16, 2018 - Precision medicine-based approach to slow or reverse biologic drivers of Alzheimer’s disease
November 16, 2018 - Study provides new insight into norovirus outbreaks, may help guide efforts to develop vaccines
November 16, 2018 - Inexpensive, portable air purifier could help protect the heart from pollution
November 16, 2018 - New 15-minute scan could help diagnose brain damage in babies up to two years old
November 16, 2018 - Deep brain stimulation not effective for treating early Alzheimer’s
November 16, 2018 - Traditional chemotherapy superior to new alternative for oropharyngeal cancers | News Center
November 16, 2018 - What This Pond Protist Does With Its Genome Will Astound You
November 15, 2018 - Researchers develop tool that speeds up analysis and publication of biomedical data
November 15, 2018 - Scientists identify mechanism used by lung cancer cells to obtain glucose
November 15, 2018 - Abnormalities in development of the brain could be involved in onset of autism, finds new study
November 15, 2018 - Soy protein equally effective as animal protein in building muscle strength
November 15, 2018 - American Academy of Pediatrics, Nov. 2-6
November 15, 2018 - Dopamine drives early addiction to heroin
November 15, 2018 - Variance in gut microbiome in Himalayan populations linked to dietary lifestyle | News Center
November 15, 2018 - Reducing Cardiovascular Disease: The Amish Way
November 15, 2018 - King’s researchers launch charter to guide organizations to engage abuse survivors in research
November 15, 2018 - Enable Injections enters into development agreements with UCB and Apellis Pharmaceuticals
November 15, 2018 - TGen North collaborates with NARBHA Institute to advance human health
November 15, 2018 - Researchers discover molecular basis for therapeutic actions of an African folk medicine
November 15, 2018 - Human Cell Atlas study of early pregnancy shows how mother’s immune system is modified
November 15, 2018 - New guidelines for detecting and managing sarcopenia to be launched in the UK
November 15, 2018 - Researchers explore role of dietary composition on energy expenditure
November 15, 2018 - Elsevier launches Entellect™ Platform, unlocking value by creating AI-ready life sciences data
November 15, 2018 - Now that cannabis is legal in Canada, let’s use it to tackle the opioid crisis
November 15, 2018 - In the Spotlight: At the intersection of tech, health, and ethics
November 15, 2018 - Traditional Glaucoma Test Can Miss Severity of the Disease
November 15, 2018 - Researchers directly connect activities of genes with instinctive behavior in male cichlids
November 15, 2018 - Salk researchers report new methods to identify AD drug candidates with anti-aging properties
New transgenic mouse model sheds light on biological causes of Parkinson’s disease

New transgenic mouse model sheds light on biological causes of Parkinson’s disease

image_pdfDownload PDFimage_print

Parkinson’s disease (PD) is a neurodegenerative disorder that presents clinically with abnormal movement and tremors at rest. In the brain, PD is marked by the accumulation of the protein, α-synuclein (αS), into clumps known as Lewy bodies, which diminish neural health. Previous research suggests abnormal αS can alter cell membrane function and lead to cell death. Investigators from Brigham and Women’s Hospital have developed a unique mouse model to induce PD-like αS aggregation, leading to resting tremor and abnormal movement control. This mouse model responds to L-DOPA, similarly to patients with PD. The research team’s results on the use of this transgenic mouse model appear this week in Neuron.

“It is difficult to find efficient treatment therapies that target αS aggregation,” said lead author Silke Nuber, PhD, an instructor in the Ann Romney Center for Neurologic Diseases at BWH. “Thus, it is necessary to develop mouse models that reflect the long-term changes, including Lewy-like aggregation of αS and an associated close PD-phenotype, to better understand the mechanisms that lead to the initiation of PD.”

In a healthy brain, this lab first reported (Bartels et al, Nature 2011) that αS can occur normally in the form of helically folded tetramers (four units of αS wound around each other), a form that resists the aggregation that abnormal αS monomers undergo. To model the brain in PD, Nuber and her team created a novel transgenic mouse that has a tetramer-lowering mutation, which leads to αS deposits, loss of dopamine and neurotoxicity.

“With these new mice, we set out to examine the upstream role of tetramer-lowering mutations and their relevance to PD,” Nuber said. “Our hypothesis was that upstream destabilization of normal tetramers to excess monomers can lead to the changes of PD.”

To examine the effect of tetramer-abrogating mutations on αS pathology, the research team created multiple mouse lines with certain αS mutations that chronically decrease the tetramers, increase free monomers and lead to neuronal dysfunction and degeneration. They then compared their new tetramer-abrogating mouse to a mouse expressing normal human αS protein and a mouse with just a single familial PD αS mutation. The mice were carefully evaluated side-by-side for key biochemical, histological and behavioral characteristics associated with PD.

The new tetramer-abrogating mouse displayed key PD-like changes, including age-dependent αS aggregation in altered neurons and distinctive abnormal movements. These changes were all derived from preventing normal αS tetramer formation. These findings strongly suggest that tetramers are required for the normal state of αS in the brain. The authors conclude that it is likely that shifting tetramers to monomers can initiate PD. They also note that the phenotype was more prominent in male mice, which is reminiscent to what occurs in PD, a finding they plan to follow up on within the framework of the Women’s Brain Initiative at BWH.

“We can now examine PD in a whole new light. We can think about stabilizing the physiological αS tetramer, an entirely novel therapeutic concept, as a means of preventing or delaying the onset of PD,” said Nuber.

“With our lab’s experience in deciphering the earliest stages of Alzheimer’s disease, we decided some time ago to apply analogous approaches to the different protein abnormality occurring in PD,” said Dennis Selkoe, MD, the senior author of the paper and the co-director of the Ann Romney Center for Neurologic Disease at BWH. “We believe this unique mouse model shows that the tetrameric form of αS we discovered in 2011 is necessary for normal neuronal function, so that abrogating the tetramer has direct PD-like consequences. This PD mouse model will provide a new route to entirely novel therapeutic approaches.”

Source:

https://www.brighamandwomens.org/

Tagged with:

About author

Related Articles