Impaired Protein Homeostasis in Neurodegenerative Diseases

Impaired Protein Homeostasis in Neurodegenerative Diseases

The below excerpt is from an article appearing in Select Science. Click on the title above to read the entire article. For a good explanation on autophagy, click on the link below the drawing to watch a video.

https://www.youtube.com/watch?v=PvnqzhtwGZU

“Learn how selective antibodies help decipher an impaired autophagy pathway in spino-bulbar muscular atrophy

Dr. Constanza Cortes, Assistant Professor in the Department of Neurology at Duke University School of Medicine, studies impaired protein homeostasis in polyglutamine diseases such as spino-bulbar muscular atrophy.

SS: What are polyglutamine diseases?

CC: Polyglutamine diseases are a family of inherited neurodegenerative disorders, all caused by expansion of a triplet-nucleotide, CAG, in the coding region of the affected genes. The most notable is Huntington’s Disease, caused by a CAG expansion in the huntingtin gene. Another polyglutamine disease is spino-bulbar muscular atrophy (SBMA), caused by a CAG expansion in the androgen receptor (AR) gene. As the CAG codon encodes for the amino acid glutamine, the resulting proteins all carry extended polyglutamine tracts, giving the name to this family of diseases.

I study SBMA, a neuromuscular condition that targets the skeletal muscle and motor neurons in the lower spinal cord. These express high levels of the mutant AR, that result in protein inclusions, accumulating in the nuclei of affected tissues. This suggests that impaired protein quality control may form the basis of the neurodegenerative phenotypes observed in SBMA.

SS: What is the focus of your research in spino-bulbar muscular atrophy (SBMA)?

CC: I focus on protein quality control mechanisms and investigate the role they may play in the pathogenesis of SBMA. Protein homeostasis (also known as proteostasis), is fundamental for the survival of neurons, and proteostasis dysfunction is a feature of many neurodegenerative diseases, including Alzheimer’s and Parkinson’s disease. Understanding the mechanisms underlying proteostasis dysfunction and uncovering novel targets for rescuing these defects may yield important therapeutic targets for diseases associated with proteostasis failure.

SS: How does impaired protein homeostasis contribute to neurodegeneration in SBMA?

CC: I have uncovered a previously unreported periphery-to-CNS signaling network originating in skeletal muscle. Using a transgenic mouse model for a gene that’s a master regulator of cellular clearance and metabolism, conditionally expressed in the skeletal muscle, I have shown improved proteostasis in the CNS during normal aging. This suggests that maintaining skeletal muscle proteostasis during aging may yield important neuroprotective benefits in the aging brain.

In agreement with this, these muscle-specific proteostasis-activated mice perform significantly better in neurocognitive testing at 18 months of age compared to their age-matched control littermates. This suggests the existence of secreted signals originating in skeletal muscle and targeting the CNS, resulting in improved proteostasis control in the brain. My current work focuses on identifying those signals and testing their ability to rescue neurodegenerative ‘proteinopathies’, including Alzheimer’s disease….” For more, click on the heading at the top of this page.

Kennedy's Disease - Beyond Motor Neurons

The link below opens a recent study published in the Journal of Neurology, Neurosurgery & Psychiatry. It explains SBMA (Kennedy’s Disease) very well. The report is not just focused on the motor neurons. It goes into detail explaining other aspects of the condition and other potential opportunities for a treatment.

Beyondmotor neurons: expanding the clinical spectrum in Kennedy’s disease

Raquel Manzano, Gianni Sorarú, Christopher Grunseich, Pietro Fratta, Emanuela Zuccaro, Maria Pennuto, Carlo Rinaldi

“…Compared with other motor neuron diseases, such as amyotrophic lateral sclerosis (ALS), disease progression is relatively slow, with muscle strength declining by 2% per year. Recent evidence has shown that the muscle atrophy in SBMA is not solely secondary to the motor neuron degeneration but also consequence of a primary myopathic process. In addition, SBMA is frequently complicated by other signs and symptoms such as gynaecomastia, impotence, testicular atrophy and metabolic changes, suggesting a multisystem involvement in the disease. These features frequently manifest early in the disease course and can contribute substantially to the morbidity. In this review, we discuss the non-motor neuron abnormalities underlining SBMA symptomatology. We propose that an improved understanding of these features not only could result in better management of the patients SBMA, but also has the potential to shed new light into the disease pathogenesis, lead to the discovery of biomarkers for disease progression and open new treatment avenues. …”

“… Motor neurons are particularly sensitive to alterations in the proteostasis network, likely due to their extreme polarisation and post-mitotic nature. On the other side, alterations of protein quality control in muscle, by tilting the balance towards increased protein degradation, are likely the underlying cause of the muscle atrophy observed in this disease. …”

I feel this information should be shared with your primary care doctors. It might help explain other symptoms not normally associated with Kennedy’s Disease.

Huntington’s breakthrough

I have mentioned in earlier articles that Huntington’s Disease share a common genetic defect. It was first reported several years ago a PubMed article links acommonality between HD, KD and SCA-1.

“…Three neurodegenerative diseases, Huntington's disease (HD), Kennedy's disease (hereditary spinobulbar muscular atrophy, SBMA), and type 1 spinocerebellar ataxia (SCA-1) have been found to share a common genetic defect: an unstable region of repeated CAG trinucleotides…”

This morning I read a BBC News report about a potential breakthrough in the treatment and possible cure of Huntington’s Disease. This appears to be another positive step forward in search of an eventual treatment or cure for Kennedy’s Disease.

Huntington’s breakthrough may stop disease

James Gallagher, Health and science correspondent, reports: “…The unstoppable death of brain cells in Huntington's leaves patients in permanent decline, affecting their movement, behaviour, memory and ability to think clearly.

• Huntington's generally affects people in their prime - in their 30s and 40s
• Patients die around 10 to 20 years after symptoms start
• About 8,500 people in the UK have Huntington's and a further 25,000 will develop it when they are older Huntington's is caused by an error in a section of DNA called the huntingtin gene.
• Normally this contains the instructions for making a protein, called huntingtin, which is vital for brain development. But a genetic error corrupts the protein and turns it into a killer of brain cells.

The treatment is designed to silence the gene…”

“…On the trial, 46 patients had the drug injected into the fluid that bathes the brain and spinal cord. The procedure was carried out at the Leonard Wolfson Experimental Neurology Centre at the National Hospital for Neurology and Neurosurgery in London. Doctors did not know what would happen. One fear was the injections could have caused fatal meningitis. But the first in-human trial showed the drug was safe, well tolerated by patients and crucially reduced the levels of huntingtin in the brain…”

Gene Therapy for Neurodegenerative Diseases

SMA News Today published an interesting article. Perhaps another opportunity for us living with Kennedy's Disease.

INT41 Gene Therapy for Neurodegenerative Diseases Granted Priority Patent Status

The patent application for gene therapy candidate1 INT41, developed by Vybion for the treatment of Huntington’s disease, spinal muscular atrophy (SMA), and other neurodegenerative diseases, was granted Track One status from the U.S. Patent and Trademark Office (USPTO).

The patent application covers the treatment’s composition and methods of use. The Track One designation gives the application priority review, allowing it to get a final decision within about a year. Track One has fewer requirements and doesn’t need a pre-examination search for the application.

“Vybion is pleased to receive Track 1 status on INT41 and anticipates rapid review and allowance,” Vybion CEO Lee Henderson said in a press release.

INT41 gene therapy was specifically designed to target neurologic diseases caused by polyQ expansions, resulting in mutant proteins that accumulate in motor neurons and subsequently lead to cellular degeneration. The gene therapy aims to detect and target the “toxic” sequence, promoting its degradation and thereby preventing its accumulation in neuronal cells. ...

... INT41 is considered a potential therapeutic strategy for other neurodegenerative diseases with similar biological features, such as spinal cerebellar ataxia, Alzheimer’s disease, and spinal and bulbar muscular atrophy (SBMA). However, the treatment has so far been more fully developed for Huntington’s, according to Vybion’s drug pipeline, and more studies are required to validate its effectiveness and safety for it and other neurodegenerative conditions. ...

To read the entire article click on the title above.

For those that want to read the actual study, follow this link. Journal of Neurodegnerative Diseases

Spreading the Word

I love to receive comments and emails from people. It means a lot to me to have readers of my blog to take the time to comment about something I wrote. This week I received an email from a young woman whose father recently was diagnosed with Kennedy’s Disease. Her message is one that needs sharing.

Spinal Bulbar Muscular Atrophy, aka Kennedy’s Disease, like so many rare neuromuscular disorders, can be devastating to a family. It takes a certain type of strength for family members, especially children, to move forward after the diagnosis. This person is not only moving forward, she is looking for ways to help spread the word and help others.

 ____________________________

Dear Bruce,

I would like to start this letter off by saying thank you for sharing your personal journey and wisdom through your writings. The KDA website and your blog have given me and my family comfort and strength.

I am 26 years old and live in Massachusetts. A few months ago, my dad was officially diagnosed with Kennedy’s Disease.

When my dad first explained to me that he had a neurodegenerative disease, it was the first time in my life I saw him as vulnerable. At first, it seemed impossible to imagine that the man who has cared for and protected me my whole life will slowly begin to depend on others. I started to think about all the little things that made him my dad. 

He is the man who tucked me in at night that checked for monsters under my bed. He is the one who gave me piggyback rides around the house, and played with me outside. He held my hand and watched me grow. I asked myself, “Will he be able to walk me down the aisle and dance with me at my wedding?” I know similar thoughts have gone through his mind as well, which is what hurts my heart the most. Yet, those are not the things that truly define him as a father. It is his quiet way of always understanding, and unyielding patience towards me. It is his reassuring presence, his unconditional love, and meaningful life lessons that make him my dad. These are the invaluable parts of my father that Kennedy’s Disease can never weaken or take away.

I’ve learned to never take another walk or hug from my dad for granted. As you have said before, living with KD is a never-ending learning process - and he has harder days ahead. It is undeniable that Kennedy’s Disease has made my father physically weaker, yet he is the strongest man I know.

Like many families who are recently diagnosed, I too, had never heard of Kennedy’s Disease. After searching long and hard for stories and information, I was disheartened by how little information I found. I then came across a post of yours that caught my attention:

Empathy - How do we reach a wider audience?

Although KDA has made significant strides since 2008 when this was posted, I still believe this issue is relevant today. With the amount of technology and access we have to the Internet, how is there still such little research and public awareness? I believe that a key part to the solution is focusing on generation Y. Millennials are now the largest generation in our nation. They learn and communicate through social media outlets, and they’re comfortable with self-education.

Being part of the ‘millennial’ generation, I like to think of myself as slightly more tech-savvy than my parents, and most people their age.  Nobody has really talked to, or informed my generation about KD, and I would love to help spread the message through a visually responsive website or different media platforms.

I think one of the reasons why more people are not more empathetic towards KD is because there are very few personal stories available for the general public to connect with. People respond and relate to a personal cause. Posting videos and visuals are one of the most effective ways to inspire individuals to support an organization and help create a larger online audience. Out of the small percentage that do know of KD, it seems like the majority think of it as an “old man’s” disease, which is a misconception that needs to be changed. It's so important for people to realize Kennedy’s Disease doesn’t just affect one man; it affects a whole family. 

Please let me know if you have any questions about me, my family or my ideas... Any feedback would be greatly appreciated. I would love to contribute in any way. We are also planning on attending the KD conference in the Fall :)

Thank you for your time and everything you do.

NORD and Trio Health collaboration for Rare Disease Patients

NORD and Trio Health to Provide Real-World Insights to Improve Access and Quality of Care for More Than 7,000 Rare Diseases

Posted by Jennifer Huron

WASHINGTON, D.C./BOSTON ― April 28, 2016 ―The National Organization for Rare Disorders (NORD), the country’s leading voice for the rare disease patient community, is collaborating with Trio Health to leverage its innovative platform to monitor real-world patients. This unique insight will allow physicians, drug manufacturers, regulatory agencies and advocacy organizations to better serve and improve patient outcomes.

“If an FDA-approved treatment exists, patients deserve to have access to it,” said Peter L. Saltonstall, president and CEO of NORD. “No one is doing anything like this to serve the 1 in 10 Americans with rare diseases and we are thrilled to partner with Trio Health as part of NORD’s advocacy and patient assistance efforts.”

The collaboration creates the first common system for gathering data on treatment access and outcomes to produce insights that improve quality of care.  It marries NORD’s commitment to patient advocacy and improving access to therapies since its founding 33 years ago with new opportunities to leverage data-driven insights. Drug manufacturers and patient advocates will have the ability to gain insights into the overall patient experience, and the unforeseen roadblocks that can undermine effectiveness.

“Our joint goal is to bring transparency to the entire patient journey,” said Brent Clough, CEO of Trio Health, which has been providing similar real-world data on more common diseases since 2013. “Trio Health is honored to partner with NORD and fill a critical knowledge gap that can ultimately improve patient care.”

Wellness Physical

I just returned from my annual wellness physical. This review is an important part of my taking ownership for my health.

A couple of weeks before the physical, I review my Kennedy’s Disease journal for the last year. Important information regarding changes to my health are highlighted and tagged for easy review. I take this information and write a year in review synopsis for my doctor. Changes in strength, capabilities, and other health issues shown including:

• What changed, improved, worsened or appeared?
• When the situation first appeared or changed?
• How long did it last?
• What impact it had on my health?

The synopsis is the first thing I discuss with my doctor. It seems to be a good starting point for other health related discussion topics. This morning’s list generated a spirited discussion concerning issues around exercise, swallowing, tongue atrophy, specialty needs in regards to remaining mobile, pneumonia, etc. The best part of these discussions is the catch-ball moments. I explain the situation, he asks follow-up questions, we discuss potential needs and options, and we end up with a course of action and/or understanding. 

The good news from today’s examination; I’ll probably live another day or two. J I am in good health. My diet is good. I am managing my Kennedy’s Disease. I have the support of my doctor should I need any help. 

 

For several years I have written about the benefits of maintaining a health and exercise journal. My previous blood workup reports are a part of this journal. At any time I can compare months or years to determine what has changed and why. If you haven’t started your journal yet, please give it a try. It might just change your life and how you live it.

Hard to Swallow?

Ed Meyerthoen, the KDA's resident expert on Kennedy's Disease posted the following message in the KDA Forum:

The KD group in Japan just published a study on exercises that they found can improve swallowing in KD patients. The paper can be found here. These exercises are quite straightforward and can be done anywhere one can lie down. A pdf of the exercises can be found here. The exercises are done 3 times a day, every day.

Head Lift Exercise Improves Swallowing Dysfunction in Spinal and Bulbar Muscular Atrophy

The PDF instructions published by Wexner Medical Center of Ohio State are easy to follow. Even though it was only a small study group and only lasted six weeks, the initial results are positive. I plan on trying the exercises and see if they will help me. 

As always is the case, before you try any new exercises, consult with your doctor and physical therapist.

Tempering hope with a dose of reality

A responder in the KDA Forum mentioned a BBC News article that showed promise on the research front. The article titled, “Range of brain diseases could be treated by single drug,” was interesting because it mentioned Huntington’s disease and that is often linked to Kennedy’s Disease in regards to the defective DNA. The report mentioned that the study was preliminary, but everything starts out as preliminary and it could eventually lead to something.

“In a study, published in Nature, they prevented brain cells dying in mice with prion disease. It is hoped the same method for preventing brain cell death could apply in other diseases. The findings are at an early stage, but have been heralded as "fascinating".


Many neuro-degenerative diseases result in the build-up of proteins which are not put together correctly - known as misfolded proteins. This happens in Alzheimer's, Parkinson's and Huntington's as well as in prion diseases, such as the human form of mad cow disease.”


Other interesting comments include:

“The idea, which has not yet been tested, is that if preventing the shutdown protects the brain in prion disease - it might work in all diseases that have misfolded proteins.
Prof Mallucci added: "What it gives you is an appealing concept that one pathway and therefore one treatment could have benefits across a range of disorders. But the idea is in its early stages. We would really need to confirm this concept in other diseases."


“Professor of Molecular Neurobiology at King's College London, Roger Morris, said it was a "breakthrough in understanding what kills neurons". He added: "There are good reasons for believing this response, identified with prion disease, applies also to Alzheimer's and other neuro-degenerative diseases. "And because it is such a general response, we already have some drugs that inhibit this response."


The more I read, the more tempering words I saw: “infancy, early stages, need to confirm, and need to see the same results in other diseases.”

I immediately sent the link to Ed, our resident Biology professor, asking for his thoughts. Ed responded back with the following:

“I have not read the paper (yet), but it has always been hoped that misfolded proteins would be a common thread in the mechanism that causes the cell death.  However, it is VERY premature to assume it actually works on other diseases, so I would be very careful how to explain it.  The implementation of such a treatment is likely many years away.”


Still, the more we understand about what causes these health conditions the better chance there is to find a potential link to the diseases and possibly even a treatment. ‘One small step’ might lead to ‘a giant leap’ along the way.