Breaking News
April 25, 2019 - Feces transplantation is effective and provides economic benefits
April 25, 2019 - Eisenhower Health first in Southern California to offer new lung valve treatment for COPD/emphysema
April 25, 2019 - Johns Hopkins researchers uncover role of neurotransmitter in the spread of aggressive cancers
April 25, 2019 - Porvair Sciences offers highly effective P3 microplate for biological sample clean-up
April 25, 2019 - Air pollution increases risk for respiratory hospitalization among childhood cancer survivors
April 25, 2019 - We are sitting more! How bad is that?
April 25, 2019 - ADHD Screening: MedlinePlus Lab Test Information
April 25, 2019 - Cellular alterations increase vulnerability of obese and diabetic individuals to infection
April 25, 2019 - Association Insurance Pushes On Despite Court Ruling
April 25, 2019 - Traditional and e-cigarette users may be more receptive to smoking cessation interventions
April 25, 2019 - Delving into tumor’s cellular lineage may offer clues for customized therapies
April 25, 2019 - Two studies uncover brain mechanisms underlying decision making process
April 25, 2019 - Cardiometabolic Risk Better ID’d in Children Reclassified to Higher BP
April 25, 2019 - How the obesity epidemic is taking a toll on our bones and joints
April 25, 2019 - E-cigarettes contaminated with dangerous microbial toxins
April 25, 2019 - Researchers document specific characteristics of storefront tobacco advertisements
April 25, 2019 - Oncotype DX-guided treatment could reduce cost for breast cancer care, study suggests
April 25, 2019 - New review highlights how lifestyle affects our genes
April 25, 2019 - Study provides evidence that blood tests can detect Alzheimer’s risk
April 25, 2019 - Computer program mimics natural speech using brain signals from epilepsy patients
April 25, 2019 - Physicians turning to antibiotic alternatives for long-term acne treatment
April 25, 2019 - Preschool Is Prime Time to Teach Healthy Lifestyle Habits
April 25, 2019 - Study finds insidious and persistent discrimination among physician mothers
April 25, 2019 - Newly identified skin-gut communication helps illuminate link between food allergy and eczema
April 25, 2019 - Thiazide use linked with reduced risk of low energy fractures in people with Alzheimer’s
April 25, 2019 - Some women are biologically more resilient than others to PTSD
April 25, 2019 - The Current issue of “The view from here” is concerned with Partnerships and Alliances
April 25, 2019 - Imaging method reveals long-lived patterns in cells of the eye
April 25, 2019 - Podcast: KHN’s ‘What The Health?’ The Abortion Wars Rage On
April 25, 2019 - Prolonged exposure therapy is more effective in treating veterans with PTSD, alcohol use disorder
April 24, 2019 - Our artificial cornea breakthrough could lead to self-assembling organs
April 24, 2019 - A Stanford black, female, gay surgery resident speaks out
April 24, 2019 - Donna Lynne on Extreme Sports, Lessons From the '60s, and Taking CUIMC to the Next Level
April 24, 2019 - Pain Clinics’ Doctors Needlessly Tested Hundreds Of Urine Samples, Court Records Show
April 24, 2019 - Researchers uncover potential clue to halt destruction of nerve cells in people with ALS
April 24, 2019 - Study uncovers reasons for poor mental health in bisexual people
April 24, 2019 - Screenings, interventions, and referrals can help adolescents overcome substance abuse
April 24, 2019 - Febrile seizures following vaccination are self-resolving and not dangerous
April 24, 2019 - Flow-UV inline UV-Visible spectrometer monitors dispersion in real time
April 24, 2019 - Rates of Marijuana Use in Cancer Patients on the Rise in U.S.
April 24, 2019 - Versatile drug may protect baby from hazards of intraamniotic infections
April 24, 2019 - Financial transparency may diminish trust in doctors, new study finds
April 24, 2019 - Calling all Riders: Velocity Extends Free Registration 
April 24, 2019 - The Homeless Are Dying In Record Numbers On The Streets Of L.A.
April 24, 2019 - Researchers use brain scans to provide better understanding of unconscious bias
April 24, 2019 - Blocking BRAF ubiquitination may be an effective treatment approach in melanoma
April 24, 2019 - Simple mobility test helps predict hospital readmission in elderly heart attack patients
April 24, 2019 - Novel fluorescence imaging system helps surgeons remove small ovarian tumors
April 24, 2019 - Uncovering the Structure of HIV Integrase to Inform Drug Discovery
April 24, 2019 - Medical Marijuana Use Rising Among Cancer Patients
April 24, 2019 - Artificial intelligence approach optimizes embryo selection for IVF
April 24, 2019 - Doctor or detective? Sleuthing mysteries in medical school
April 24, 2019 - CUIMC Community Gives Blood During Spring 2019 Columbia University Blood Drive
April 24, 2019 - Americans Overwhelmingly Want Federal Protections Against Surprise Medical Bills
April 24, 2019 - Making Laboratories More Efficient with the Most Modern LIMS on the Market
April 24, 2019 - Treating cancer patients with personalized, combination therapies improves outcomes
April 24, 2019 - Researchers engineer new molecules to help stop lung cancer
April 24, 2019 - Acupuncture can be a wonderful tool for preventing number of diseases
April 24, 2019 - Daily life disability before hip replacement may predict poor post-operative outcomes
April 24, 2019 - Study finds involuntary staying in housing estates to be a potential health risk
April 24, 2019 - Older kidney disease patients starting dialysis die at higher rates than previously thought
April 24, 2019 - Time-restricted eating shows promise for controlling blood glucose levels
April 24, 2019 - Ambiguous genitalia in newborns may be more common than previously thought
April 24, 2019 - Research provides important insight on the brain-body connection
April 24, 2019 - In 10 Years, Half Of Middle-Income Elders Won’t Be Able To Afford Housing, Medical Care
April 24, 2019 - Researchers study how E. coli clones have become major cause of drug-resistant infections
April 24, 2019 - Bacterial and fungal toxins found in popular electronic cigarettes
April 24, 2019 - Factors affecting absorption of ‘sunshine vitamin’ during spring/summer months
April 24, 2019 - Texting helps improve medication adherence, health outcomes for patients with schizophrenia
April 24, 2019 - Cochrane Review looks at different ways to use nicotine replacement therapies
April 24, 2019 - New review on relationship between COPD and Type 2 diabetes
April 24, 2019 - Brain areas linked to memory and emotion aid odor navigation in humans
April 24, 2019 - Brain stimulation reverses age-related memory loss
April 24, 2019 - Amid Opioid Prescriber Crackdown, Health Officials Reach Out To Pain Patients
April 24, 2019 - $4 million NIH award will help establish UCI Skin Biology Resource-based Center
April 24, 2019 - Cancer drugs reprogram genes in breast tumors to prevent endocrine resistance, finds study
April 24, 2019 - Combination-imaging technique provides new window into macaque brain connections
April 24, 2019 - Researchers identify new allergen responsible for allergy to durum wheat
April 24, 2019 - Researchers define role of rare, influential cells in the bone marrow
April 24, 2019 - DNA rearrangement may predict poor outcomes in multiple myeloma
Genetic model offers elegant tool for testing Parkinson’s disease therapies

Genetic model offers elegant tool for testing Parkinson’s disease therapies

image_pdfDownload PDFimage_print
Immunohistochemistry for alpha-synuclein showing positive staining (brown) of an intraneural Lewy-body in the Substantia nigra in Parkinson’s disease. Credit: Wikipedia

For the past decade, Parkinson’s disease researchers have relied on the experimental equivalent of using a sledgehammer to tune a guitar to test new therapies for the disease. This may be a reason clinical trials of promising neuroprotective drugs fail. But, in new research published today in Nature Parkinson’s Disease, University of British Columbia researchers may have found the ideal tool for the job.

“We believe we’ve found an approach that is most relevant to humans, in that our models of gene dysfunction mimic the etiology of Parkinson’s disease rather than its pathology— meaning its beginning rather than its end,” says Matthew Farrer, the study’s lead investigator and a researcher at the Djavad Mowafaghian Centre for Brain Health at UBC. “This means we’re looking at the disease before it becomes symptomatic, before it begins affecting an individual’s motor skills or cognition.”

Parkinson’s disease symptoms are associated with the progressive loss of dopamine-producing nerve cells. Over time, these cells effectively become out of tune, and eventually they stop working altogether.

Until now, the best available experimental models of the disease were based on flooding the brain with alpha-synuclein—a protein in the brain that, when it accumulates abnormally into clumps, is linked to Parkinson’s—or using neurotoxins to destroy dopamine-producing cells. These conventional models exhibit the classic motor and behavioural symptoms of the disease, which is why they have been widely adopted by the Parkinson’s field, but the sledgehammer approach to inducing the disease means the cells die—the guitar is smashed—before any of the subtle changes in the tune can be measured.

According to Parkinson Canada, the disease affects about 100,000 Canadians and 7 million people worldwide. A great many patients are put at elevated risk for disease because of mutations in a gene called LRRK2—a discovery Farrer and colleagues made in 2004.

So far, no LRRK2-specific drugs developed as a neuroprotective treatment for Parkinson’s have achieved FDA approval for the treatment of Parkinson’s disease, and some companies have abandoned their LRRK2 programs due to potential side effects.

The new model, developed by Farrer and his team could offer the precise tool that researchers have long hoped would deliver the impact of LRRK2 inhibitors and other disease-modifying drugs.

The model—known as a VPS35 D620N knock-in (VKI)—induces the biology of a disease-causing gene rather than the symptoms of the disease. Although the model shows no behavioral signs of Parkinson’s, their new study found the changes in biology are clear and elegantly precise. As a tool for preclinical research, it gives scientists something to measure and, ultimately, to fix with promising neuroprotective drugs.

The lab’s recent work to characterize the VKI model shows it is critically important in dopamine neurotransmission, where it regulates the activity-dependent recycling of the dopamine transporter. While the team was the first to suspect a relationship between LRRK2 and VPS35 in 2012, when they initially discovered the role of VPS35 in Parkinson’s, it is novel to observe activity-dependent changes in dopamine release and reuptake due to a single point mutation.

“What’s really exciting for us is that everything we’re seeing is pointing to an early change in synaptic activity,” says Igor Tatarnikov, a graduate student working with Farrer to characterize the VKI model. “It’s something we might rescue with the right drugs, and something we might visualize, because LRRK2 and VPS35 affect the same biological pathway. We’re hoping to use PET imaging to provide a clinically relevant biomarker, which would be relevant beyond genetic forms of the disease. In the future, our hope is that people who carry the VPS35 mutation may be an ideal group for clinical trials.”

“VKI mice provide one of the tools to quantify the minimal dose of LRRK2 kinase inhibitors to see neuroprotective benefits, and so advance therapeutic trials in human patients,” says Farrer. “Imagine if we could begin helping people at risk of Parkinson’s disease as early as their 40s and 50s. We believe we’re in the right key with LRRK2 and VPS35, now it’s just a matter of arranging the notes.”


Explore further:
Parkinson’s treatments being developed could benefit most people with the disease

Provided by:
University of British Columbia

Tagged with:

About author

Related Articles