Breaking News
February 21, 2019 - Gaming system helps with autism diagnosis
February 21, 2019 - Heart Disease: Six Things Women Should Know
February 21, 2019 - More States Say Doctors Must Offer Overdose Reversal Drug Along With Opioids
February 21, 2019 - Researchers explore case studies focused on industries that kill more people than employed
February 21, 2019 - Intense exercise, fasting and hormones can enhance waste-protein removal, study shows
February 21, 2019 - Scientists can monitor brain activity to predict epileptic seizures few minutes in advance
February 21, 2019 - Study quantifies hepatic and intestinal mRNA expression of Ugt isoforms in rats
February 21, 2019 - ‘Apple-Shaped’ Body? ‘Pear-Shaped’? Your Genes May Tell
February 21, 2019 - Can we repair the brain? The promise of stem cell technologies for treating Parkinson’s disease
February 21, 2019 - Trump Plan To Beat HIV Hits Rough Road In Rural America
February 21, 2019 - PENTAX Medical introduces new electrosurgical and argon plasma coagulation platforms
February 21, 2019 - Trump plan to beat HIV hits rough road in rural America
February 21, 2019 - Eating blueberries every day could help decrease blood pressure
February 21, 2019 - ‘No Second Chances’ report calls for new measures to combat cardiovascular disease in Australia
February 21, 2019 - Mayo clinic researchers discuss local case studies of leprosy
February 21, 2019 - Scientists demonstrate key role of salt in allergic immune reactions
February 21, 2019 - Experts propose revising the criteria for diagnosis of Parkinson’s disease
February 21, 2019 - The med student and the machine
February 21, 2019 - Hey, Hey! Ho, Ho! Is Striking For School Nurses The Way To Go?
February 21, 2019 - Latest research encourages children to move out and learn through physical activity
February 21, 2019 - Proper oral hygiene and regular visits to dentist can promote heart health
February 21, 2019 - New, versatile technique for remote control of transplanted cells in Parkinson’s
February 21, 2019 - Why melanoma tumors in the brain may be worse?
February 21, 2019 - New project aims to improve lung disease care in Appalachia
February 21, 2019 - Drug increases melanin production in some people with albinism
February 21, 2019 - Over 1 in 3 adults miss the mark on protein, finds study
February 21, 2019 - CymaBay Therapeutics Announces Seladelpar Granted Breakthrough Therapy Designation by the FDA for the Treatment of Primary Biliary Cholangitis
February 21, 2019 - A correlation between obesity and income has only developed in the past 30 years
February 21, 2019 - Baby, then work: An effort to help resident-parents in emergency medicine
February 21, 2019 - Heavy cigarette smoking could damage vision, say researchers
February 21, 2019 - Some drug combinations may be more effective than others for schizophrenic patients
February 21, 2019 - Combination of common antibiotics can eliminate multi-drug resistant E. coli
February 21, 2019 - Number of calls to U.S. Poison Control regarding kratom exposure increased
February 21, 2019 - New computational tool searches for factors that cause specific diseases
February 21, 2019 - New method to assess effectiveness of psychotherapies for social anxiety disorder
February 21, 2019 - New technology measures hormones that influence reproductive health efficiently
February 21, 2019 - Bat influenza viruses could potentially attack the cells of humans and livestock
February 21, 2019 - Immunotherapeutic antibody therapy to kill cancer has now progressed to patient testing
February 21, 2019 - Johns Hopkins scientists find new compound that may prevent reperfusion injury
February 21, 2019 - Researchers develop new way to deliver treatment for cartilage regeneration
February 21, 2019 - Study sheds new light on left ventricular dysfunction in ischemic heart disease
February 21, 2019 - New technique could expedite cancer diagnosis, lead to better patient outcomes
February 21, 2019 - New map of infant brain may aid early diagnosis of autism
February 21, 2019 - Human consciousness depends on the brain’s ability to maintain dynamics of neural activity
February 21, 2019 - Harmony Biosciences Announces File Acceptance Of Its New Drug Application For Pitolisant
February 21, 2019 - Medications could fill treatment gap for adolescents with obesity
February 21, 2019 - New antibiotics are desperately needed: Machine learning could help | News Center
February 21, 2019 - Researchers develop new computer game for dementia carers
February 21, 2019 - University of Dundee partners with Takeda to develop new treatments for tau pathology
February 21, 2019 - Influenza vaccine may be less effective in elderly patients, finds study
February 21, 2019 - Researchers explain why T cells lose their protective ability in inflamed tissues
February 21, 2019 - New optimization method rapidly analyzes nanomedicines for cancer treatment
February 21, 2019 - Viruses in the intestinal tracts can lead to islet autoimmunity and Type 1 diabetes
February 21, 2019 - Link between dietary fatty acid intake and hypertension found to be influenced by diabetes status
February 21, 2019 - FDA Approves Esperoct (turoctocog alfa pegol, N8-GP) for Hemophilia A
February 21, 2019 - ‘Boy erased’—why conversion therapies and ex-gay ministries should be outlawed
February 21, 2019 - Titia de Lange to give annual McCormick Lecture on March 8 | News Center
February 21, 2019 - Study reveals how helper T cells support memory cells to function optimally
February 21, 2019 - Autistic children with co-occurring ADHD have greater adaptive behavior impairments
February 21, 2019 - Elevated levels of key cellular process implicated in intestinal inflammation and IBD
February 20, 2019 - Over Half of Hip Replacements Expected to Last 25 Years
February 20, 2019 - Microscopic eye movements affect how we see contrast
February 20, 2019 - Computer vs. patient: Fighting for residents’ attention | News Center
February 20, 2019 - New “Smart Drug” Shows Promise for Metastatic Triple-Negative Breast Cancer
February 20, 2019 - Researchers develop large-scale window material for high-efficiency PM2.5 capture
February 20, 2019 - Widespread confusion among consumers on food date labels lead to unnecessary discards
February 20, 2019 - Researchers unlock plant’s secret of producing specialized metabolites
February 20, 2019 - Newly released national framework identifies obstacles to improving EMS systems
February 20, 2019 - Exercise can shift human body clock depending on time when people work out
February 20, 2019 - Female adolescent blood donors more likely to have iron deficiency and related anemia
February 20, 2019 - Rubicon level linked to inhibition of autophagic process
February 20, 2019 - Researchers find potential therapeutic strategy to treat Alzheimer’s
February 20, 2019 - New forms of older anti-cancer agent appear to enhance immune response to fight melanoma
February 20, 2019 - Health Tip: Eat Less Saturated Fat
February 20, 2019 - Sleeping in contact lenses puts you at risk of dangerous infection
February 20, 2019 - “We should study that!”: How a nurse-scientist found her passion
February 20, 2019 - Cervical microbiome may influence HPV infection more than previously thought
February 20, 2019 - Sausage mislabeling in Canada is down, new study finds
February 20, 2019 - Study shows blood pressure benefits of morning exercise for older overweight/obese adults
February 20, 2019 - New screening method could catch organ rejection much earlier without a biopsy needle
Mutations, CRISPR, and the biology behind movement disorders

Mutations, CRISPR, and the biology behind movement disorders

image_pdfDownload PDFimage_print
CRISPR (= Clustered Regularly Interspaced Short Palindromic Repeats) + DNA fragment, E.Coli. Credit: Mulepati, S., Bailey, S.; Astrojan/Wikipedia/ CC BY 3.0

Scientists at the RIKEN Center for Brain Science (CBS) in Japan have discovered how mutations related to a group of movement disorders produce their effects. Published in Proceedings of the National Academy of Sciences, the study found three ways in which mutations affecting the IP3R1 protein can affect the chemical balance of neurons in the brain, ultimately leading to the degeneration of motor control.

Among the many types of degenerative movement disorders, spinocerebellar ataxias are a group that result from dysfunction in the cerebellum. The cerebellum allows smooth and coordinated movements such as walking and speaking. Spinocerebellar ataxias come in many types with different genetic origins. Recently, a spinocerebellar ataxia with very early infantile onset (SCA29) was shown to be associated with mutations that affect the protein receptor IP3R1, which is especially common in neurons of the cerebellum. Led by Katsuhiko Mikoshiba, the group at RIKEN CBS conducted a series of experiments to determine exactly how the different mutations related to SCA29 affect IP3R1 function within cells.

Studying mutations in IP3Rs turns out to be difficult because nearly all cells have one or more of the three types. Although other researchers have made cells lines in which all three types have been deleted, the process of introducing mutant genes into them is inefficient and time consuming. Mikoshiba and his group used CRISPR genome editing technology to create cells in which all three IP3R genes were disrupted. Introducing mutant or wildtype IP3Rs into these cells could be done very efficiently, which allowed them to complete the study much more quickly than could have been achieved otherwise.

The team looked at over 10 different mutations related to SCA29. “Surprisingly,” notes first author Hideaki Ando, “all of the SCA29 pathological mutations identified within or near the place that IP3 attaches to IP3R1 completely (not partially) blocked the calcium-releasing activity of IP3R1.”

Calcium is crucial for many cell functions, including signaling between neurons. When not being used, it is stored within cells. When IP3 attaches to IP3R1, it allows calcium to pass through so it can be released from storage when needed. By blocking calcium release, the SCA29 mutations prevent calcium from being able to do its job.

The team did further tests to determine how the different mutations disrupted calcium release. They found that in 9 of 12 mutations near the binding region, IP3 was prevented from binding to the receptor.

Two other mutants indirectly affected IP3R1 activity through mutations affecting the binding site of another protein—CA8. Normally when CA8 binds to the receptor, calcium release is suppressed. However, in the mutants, calcium release was higher than normal. CA8 mutations have also been identified in people with congenital ataxia and mental retardation. The team of scientists investigated how these mutations affected calcium flow through IP3R1, and found that they also prevented normal suppression of calcium release.

Understanding these molecular details mutations in IP3R1 is important for developing effective treatments. Ando explains, “Now we know that spinocerebellar ataxias can result from both suppressed or enhanced calcium release though the IP3 type 1 receptor. Therefore, drug development that enhances or inhibits IP3R1 activity may lead to effective treatments for these disorders. In fact, development of IP3R1 agonists or antagonists should benefit from our previous research in which we revealed the crystal structure of IP3R1.”


Explore further:
New insights into control of neuronal circuitry could lead to treatments for an inherited motor disorder

More information:
Hideaki Ando el al., “Aberrant IP3 receptor activities revealed by comprehensive analysis of pathological mutations causing spinocerebellar ataxia 29,” PNAS (2018). www.pnas.org/cgi/doi/10.1073/pnas.1811129115

Journal reference:
Proceedings of the National Academy of Sciences

Provided by:
RIKEN

Tagged with:

About author

Related Articles