Rapid onset of motor deficits in a mouse model of spinocerebellar ataxia type 6 precedes late cerebellar degeneration

Spinocerebellar ataxia type 6 (SCA6) is an autosomal dominant cerebellar ataxia that has been associated with loss of cerebellar Purkinje cells.

Disease onset is typically midlife, although it can vary widely from late teens to old age in SCA6 patients. 

Our study focused on an SCA6 knock-in mouse model with a hyper-expanded (84X) CAG repeat expansion that displays midlife-onset motor deficits at ∼7 months old, reminiscent of mid-life onset symptoms in SCA6 patients, although a detailed phenotypic analysis of these mice has not yet been reported. Here, we characterize the onset of motor deficits in SCA684Q mice using a battery of behavioral assays to test for impairments in motor coordination, balance, and gait. We found that these mice performed normally on these assays up to and including at 6 months, but motor impairment was detected at 7 months with all motor coordination assays used, suggesting that motor deficits emerge rapidly during a narrow age window in SCA684Q mice. In contrast to what is seen in SCA6 patients, the decrease in motor coordination was observed without alterations in gait. 

No loss of cerebellar Purkinje cells or striatal neurons were observed at 7 months, the age at which motor deficits were first detected, but significant Purkinje cell loss was observed in 2-year-old SCA684Q mice, arguing that Purkinje cell death does not significantly contribute to the early stages of SCA6.

Significance Statement: 

We confirm that disease onset in an 84Q-hyperexpanded polyglutamine mouse model of spinocerebellar ataxia type 6 (SCA6) occurs at 7 months of age, in agreement with a previous study by Watase and colleagues (2008). We characterize disease onset more precisely using a barrage of behavioral tests at multiple ages, and identify that motor coordination abnormalities emerge in a narrow time window between 6 and 7 months, in contrast to the variable age of onset observed in human patients. 

We find that Purkinje cell degeneration occurs in this SCA6 mouse model at 2 years, nearly 1.5 years after the onset of motor deficits, demonstrating that Purkinje cell loss is not necessary for early SCA6 disease symptoms.

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Rapid onset of motor deficits in a mouse model of spinocerebellar ataxia type 6 precedes late cerebellar degeneration, Sriram Jayabal, Lovisa Ljungberg, Thomas Erwes, Alexander Cormier, Sabrina Quilez, Sara El Jaouhari, Alanna J. Watt, eneuro Dec 2015, DOI: 10.1523/ENEURO.0094-15.2015

Positive interim results from clinical study of Cabaletta in OPMD

On October 27, 2015 BioBlast Pharma Ltd. announced positive interim results from a Phase 2 open label clinical study of Cabaletta®, in 25 patients with oculopharyngeal muscular dystrophy (OPMD).

OPMD

OPMD is a rare progressive muscle-wasting disease characterized by severe swallowing difficulties leading to malnutrition, dehydration, and aspiration of food into the lungs, as well as more generalized, progressive muscle weakness. Aspiration pneumonia and severe emaciation are frequently the cause of death.

Study

The study was designed as a proof-of-concept open-label clinical study in 74 patients for 24 weeks, following which all patients would be randomized into a treatment arm or non-treatment control group, and followed for an additional 12 months in a continuation study. The primary objective was to assess the safety and tolerability of Cabaletta. Secondary endpoints were to determine if Cabaletta improves or prevents worsening of OPMD disease markers.

As previously reported, based on the positive signals seen in the first 25 patients enrolled in Canada and Israel, further recruitment has been terminated, with the aim of beginning a Phase 3 study.

Although unplanned, an analysis was done on clinical data accumulated as of September 1, 2015 on these 25 patients.

• Cabaletta was observed to be safe and well-tolerated with no drug-related serious adverse events. 
• Statistically significant improvement or numerical improvement versus baseline, was observed on multiple efficacy endpoints related to dysphagia.
• Patients showed a statistically significant improvement in their lower extremities muscle strength versus baseline, and showed numerical improvement in other muscle strength and function tests.

"The detailed analysis of the interim results of the Phase 2 Cabaletta therapy trial for OPMD are very encouraging," stated Bernard Brais, MD, M.Phil., PhD, FRCP(C), Professor, Department of Neurology and Neurosurgery and Human Genetics, Faculty of Medicine, McGill University, Co-director Rare Neurological Diseases Group at the Montreal Neurological Institute, and Principal Investigator in the study. "Since OPMD is a chronically progressive muscular dystrophy, we felt it was optimistic to expect more than a stabilization of symptoms. In fact, the data suggest that most participants improved across multiple clinical endpoints with significant swallowing improvements, suggesting that the drug may lead to early benefits. These results are quite promising and I look forward to the confirmation of the results in the planned placebo controlled Phase 3 study which could, for the first time, show rapid and chronic improvement in a late-onset muscular dystrophy."

Cabaletta and SCA3

"The interim results for OPMD, specifically with respect to dysphagia and muscle strength and function, give us insight into the potential of Cabaletta for use in other protein aggregation-related diseases, such as spinocerebellar ataxia type 3 (SCA3 or Machado Joseph disease), another devastating hereditary disease in which we are planning a pivotal Phase 3 study in the U.S. and E.U.," Mr. Foster continued.   

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 Press release BioBlast.       

What happens if you try to park in a disabled parking space?

More than 30% of the drivers in Russia take disabled parking spaces without caring about the signs on the ground.

Dislife, a Russian non-profit organisation, came up with a powerful campaign to stop this inconsiderate behaviour. They installed projections of a real disabled person that popped up every time a non-disabled driver tried to park in their space. Special cameras verified the presence of the disabled sticker on their windshields and if no sticker was detected, the hologram would appear to confront the driver.

Watch the stunt in action below.

Funding for European Spinocerebellar Ataxia Type 3 Disease Initiative (ESMI)

Twenty one research projects have won a total of €35 million (£25.7 million) in a transnational scheme to boost research into neurodegenerative diseases, according to an announcement made by the EU Joint Programme – Neurodegenerative Disease Research (JPND) today. The winning projects will help researchers to better understand, treat and eventually prevent a wide range of debilitating neurodegenerative diseases. Neurodegenerative diseases are one of the toughest medical and economic challenges facing our global community.

The initiative aims to increase coordination of European research efforts in this area and 30 countries currently participate.

European Spinocerebellar Ataxia Type 3 / Machado-Joseph Disease (ESMI)

Coordinator: 

Thomas Klockgether, Deutsches Zentrum für Neurodegenerative Erkrankungen e.V. (DZNE), Bonn, Germany.

Partners:

Paola Giunti, University College London (UCL), United Kingdom
Manuela Lima, University of the Azores Ponta Delgada, Portugal
Luis Pereira de Almeida, University of Coimbra, Portugal
Olaf Rieß, University of Tübingen, Germany
Bart P.C. van de Warrenburg, Radboud University Medical Center Nijmegen, Netherlands

Research proposal 

Spinocerebellar ataxia type 3/Machado-Joseph disease (SCA3) is worldwide the most common autosomal dominantly inherited ataxia disorder. Currently, there is no treatment for SCA3. However, as there is an advanced understanding of the molecular mechanisms underlying SCA3, new therapeutic approaches are being developed, and the SCA3 field is entering a phase of intense trial activity. 

To enable interventional trials, availability of large cohorts that consist of preclinical mutation carriers and mildly affected patients is mandatory. For this purpose, the European Spinocerebellar Ataxia Type 3/Machado-Joseph Disease Initiative (ESMI) will set up a trial ready cohort by bringing together 7 European cohorts and 1 US cohort which together comprise approximately 900 subjects. 

The group will integrate the existing data in a common database and apply standardized and quality-controlled clinical assessment, MRI and biobanking protocols. A major part of the initiative will be the development and validation of innovative assessment instruments and disease markers, including a new highly sensitive motor test battery, diffusion-tensor imaging (DTI), automated MRI volumetric evaluation and blood as well as CSF markers based on transcript profiling and disease protein (ataxin-3) measurement. In addition, the impact of lifestyle on disease evolution will be assessed by measuring physical activity with ambulatory sensor-based activity recording and appropriate questionnaires. 

By exploiting the data obtained in this cohort,  a revised model of SCA3 disease evolution will be developed  that conceives the preclinical (pre-ataxia) stage and the ataxia stage as the graded manifestation of one disease process, and that will take lifestyle factors into account. 

The research directly impacts not only on feasibility and design of interventional trials, but also on routine health care because the new instruments, such as automated activity measurement and MRI analysis, can be used in diagnosis and routine management of ataxia patients. The European and national ataxia patient organizations are directly involved in planning and management of this project.  

100 Trains. The global charity event of 2016

A series of charity walks, and rolls (for wheelchair users), along the route of a 50,000 km train journey will be organised.

The trains that are included in this journey, are some of the highest, longest and most iconic trains on Earth; passing through some of the most beautiful and wild landscapes on the planet.

The entire, 50,000 km, journey will restart in 2016 - to raise vital funds for Ataxia UK and as a vehicle to raise global awareness of ataxia and to serve as a vehicle to unite ataxia sufferers, supporters and charities worldwide.

How you can be part of this journey

Organizer: "The journey will start on the 23rd of January next year, with a Walk'n'Roll through Hyde Park in London (my 50th birthday & I can't think of a better way of marking the occasion). Everyone, whether a London resident or visitor, ataxia sufferer or not, is invited to join me for a gentle stroll through London's finest park."

The continuation of the journey is being funded, in no small part, by the Friends of 100 Trains - a group of well-wishers (many complete strangers) who wish to be part of this journey (even if simply watching, as the journey unfolds, from the comfort of their very own armchair). ANYONE can become a "Friend" of the journey.

And as a way of thanking "Friends" for their vital support, their websites, Twitter and Facebook pages are listed. Additionally, their Twitter accounts are listed on a dedicated Twitter list at: Friends of 100 Trains.

A bit of history

The original journey, from Scotland to Siberia, was undertaken, and ultimately abandoned in Siberia, in 2013. Over 21,000 km from Glasgow in Scotland, through central and northern Europe, western Russia to Novosibirsk (Siberia).

On reaching Novosibirsk, it became obvious that a previously minor "balance" condition was progressively worsening, and that seeking medical attention might be a wise idea.

So the journey was very reluctantly abandoned, and the initiator returned to Scotland for what would turn out to be 2 years of medical tests.

"On returning to Scotland, it took a never-ending stream of doctors and neurologists almost 2 years to identify the cause of my deteriorating health. And it wasn't good news: I am suffering from a form of ataxia. Late onset Spinocerebellar Ataxia in my case."

"Ataxia? Never heard of it? Neither had I. And we're not alone. Around 91% of the UK population have never heard of it either (one of my aims for this journey, is to put a huge dent in that 91% figure!)."

"So now I will attempt the entire 50,000 km journey again. Only this time, the journey will be done in a number of smaller stages (due to the nature of my ataxia). Plus, I'll be taking part in fundraising walks in many of the cities I pass through - raising vital research funds for ataxia research, and uniting ataxia sufferers and supporters worldwide. "

Investigating a new treatment in SCA14

This study will expand on the previous preliminary results which found a reduction of glutathione
in the cerebellum of people with SCA14. 

Glutathione is an antioxidant that ordinarily protects cells from damage by oxidative stress, thus a reduction in glutathione could be linked to cerebellar degeneration. Oxidative stress occurs when the production of reactive oxygen is greater than the body's ability to detoxify the reactive intermediates. This imbalance leads to oxidative damage to proteins, molecules, and genes within the body. Since the body is incapable of keeping up with the detoxification of the free radicals, the damage continues to spread.

 

Ball-and-stick model of the glutathione molecule

Research

The researchers plan to use a non-invasive technique called MR Spectroscopy to detect changes in the level of the anti-oxidant glutathione in the brain in 12 people with SCA14.

The team at The Charité - University Medicine Berlin want to find a new, more reliable way of specifically measuring the level of glutathione reduction. This could potentially pave the way for a new therapy in the future which targets glutathione reduction. It could also potentially be used to detect for any glutathione reductions in other ataxias in the future. 

For example, a small preliminary study found that the drug N-Acetylcystein could be used to increase glutathione levels in a certain part of the brain in people with Parkinson’s disease. 

Although SCA14 is a rare form of ataxia it might be under-diagnosed as it is not routinely tested for in all hospitals. However, if a treatment were found the need for diagnosis would be even more important.

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The study will be jointly funded by Ataxia UK and the German ataxia charity DHAG.

Dr Sarah Doss and Dr Jan Rinnenthal, The Charité - University Medicine Berlin

Article Ataxia UK 

Neuronal atrophy in SCA1: a non-specific event or a compensatory response?

Neuronal atrophy in neurodegenerative diseases is commonly viewed as an early event in a continuum that ultimately results in neuronal loss.

In a mouse model of SCA1, the hypothesis was tested that cerebellar Purkinje neuron atrophy serves an adaptive role rather than being simply a nonspecific response to injury. In acute cerebellar slices from SCA1 mice, Purkinje neuron pacemaker firing is initially normal but, with the onset of motor dysfunction, becomes disrupted, accompanied by abnormal depolarization. Remarkably, subsequent Purkinje cell atrophy is associated with a restoration of pacemaker firing. The restoration of SCA1 Purkinje neuron firing correlates with the recovery of the density of these potassium channels that accompanies cell atrophy. 

These results suggest that Purkinje neuron dendritic remodeling in ataxia is an adaptive response to increases in intrinsic membrane excitability. Similar adaptive remodeling could apply to other vulnerable neuronal populations in neurodegenerative disease.

Conclusion

In neurodegenerative disease, neuronal atrophy has long been assumed to be an early nonspecific event preceding neuronal loss. However, in a mouse model of spinocerebellar ataxia type 1 (SCA1),  a previously unappreciated compensatory role for neuronal shrinkage. is identified.  Purkinje neuron firing in these mice is initially normal, but is followed by abnormal membrane depolarization resulting from a reduction in potassium channels. Subsequently, these electrophysiological effects are counteracted by cell atrophy, which by restoring normal potassium channel membrane density, re-establishes pacemaker firing. Reversing the initial membrane depolarization improved motor function and Purkinje neuron morphology in the SCA1 mice. These results suggest that Purkinje neuron remodeling in ataxia is an active compensatory response that serves to normalize intrinsic membrane excitability.

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Neuronal Atrophy Early in Degenerative Ataxia Is a Compensatory Mechanism to Regulate Membrane Excitability, James M. Dell'Orco et al., The Journal of Neuroscience, 12 August 2015, 35(32): 11292-11307; doi: 10.1523/JNEUROSCI.1357-15.2015