Altered protein secretion in Batten disease

ABSTRACT The neuronal ceroid lipofuscinoses (NCLs), collectively known as Batten disease, are a group of neurological diseases that affect all ages and ethnicities worldwide. There are 13 different subtypes of NCL, each caused by a mutation in a distinct gene. The NCLs are characterized by the accumulation of undigestible lipids and proteins in various cell types. This leads to progressive neurodegeneration and clinical symptoms including vision loss, progressive motor and cognitive decline, seizures, and premature death. These diseases have commonly been characterized by lysosomal defects leading to the accumulation of undigestible material but further research on the NCLs suggests that altered protein secretion may also play an important role. This has been strengthened by recent work in biomedical model organisms, including Dictyostelium discoideum, mice, and sheep. Research in D. discoideum has reported the extracellular localization of some NCL-related proteins and the effects of NCL-related gene loss on protein secretion during unicellular growth and multicellular development. Aberrant protein secretion has also been observed in mammalian models of NCL, which has allowed examination of patient-derived cerebrospinal fluid and urine for potential diagnostic and prognostic biomarkers. Accumulated evidence links seven of the 13 known NCL-related genes to protein secretion, suggesting that altered secretion is a common hallmark of multiple NCL subtypes. This Review highlights the impact of altered protein secretion in the NCLs, identifies potential biomarkers of interest and suggests that future work in this area can provide new therapeutic insight.

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Neonatal brain-directed gene therapy rescues a mouse model of neurodegenerative CLN6 Batten disease

Human Molecular Genetics ◽

10.1093/hmg/ddz210 ◽

2019 ◽

Vol 28 (23) ◽

pp. 3867-3879 ◽

Cited By ~ 6

Author(s):

Sophia-Martha kleine Holthaus ◽

Saul Herranz-Martin ◽

Giulia Massaro ◽

Mikel Aristorena ◽

Justin Hoke ◽

...

Keyword(s):

Gene Therapy ◽

Mouse Model ◽

Motor Coordination ◽

Transmembrane Protein ◽

Batten Disease ◽

Premature Death ◽

Neuronal Ceroid Lipofuscinoses ◽

Therapeutic Effects ◽

Lysosomal Storage ◽

Enzyme Replacement

Abstract The neuronal ceroid lipofuscinoses (NCLs), more commonly referred to as Batten disease, are a group of inherited lysosomal storage disorders that present with neurodegeneration, loss of vision and premature death. There are at least 13 genetically distinct forms of NCL. Enzyme replacement therapies and pre-clinical studies on gene supplementation have shown promising results for NCLs caused by lysosomal enzyme deficiencies. The development of gene therapies targeting the brain for NCLs caused by defects in transmembrane proteins has been more challenging and only limited therapeutic effects in animal models have been achieved so far. Here, we describe the development of an adeno-associated virus (AAV)-mediated gene therapy to treat the neurodegeneration in a mouse model of CLN6 disease, a form of NCL with a deficiency in the membrane-bound protein CLN6. We show that neonatal bilateral intracerebroventricular injections with AAV9 carrying CLN6 increase lifespan by more than 90%, maintain motor skills and motor coordination and reduce neuropathological hallmarks of Cln6-deficient mice up to 23 months post vector administration. These data demonstrate that brain-directed gene therapy is a valid strategy to treat the neurodegeneration of CLN6 disease and may be applied to other forms of NCL caused by transmembrane protein deficiencies in the future.

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Aggregation chimeras provide evidence of in vivo intercellular correction in ovine CLN6 neuronal ceroid lipofuscinosis (Batten disease)

10.1101/2021.12.06.471461 ◽

2021 ◽

Author(s):

Lucy A. Barry ◽

Graham W. Kay ◽

Nadia L. Mitchell ◽

Samantha J. Murray ◽

Nigel P. Jay ◽

...

Keyword(s):

Vision Loss ◽

Inflammatory Responses ◽

Neuronal Ceroid Lipofuscinosis ◽

Batten Disease ◽

Brain Regions ◽

Glial Activation ◽

Neuronal Ceroid Lipofuscinoses ◽

Lysosomal Storage ◽

Storage Body

AbstractThe neuronal ceroid lipofuscinoses (NCLs; Batten disease) are fatal, mainly childhood, inherited neurodegenerative lysosomal storage diseases. Sheep affected with a CLN6 form display progressive regionally defined glial activation and subsequent neurodegeneration, indicating that neuroinflammation may be causative of pathogenesis. In this study, aggregation chimeras were generated from homozygous unaffected normal and CLN6 affected sheep embryos, resulting in seven chimeric animals with varied proportions of normal to affected cells. These sheep were classified as affected-like, recovering-like or normal-like, based on their cell-genotype ratios and their clinical and neuropathological profiles.Neuropathological examination of the affected-like animals revealed intense glial activation, prominent storage body accumulation and severe neurodegeneration within all cortical brain regions, along with vision loss and decreasing intracranial volumes and cortical thicknesses consistent with ovine CLN6 disease. In contrast, intercellular communication affecting pathology was evident at both the gross and histological level in the normal-like and recovering-like chimeras, resulting in a lack of glial activation and rare storage body accumulation in only a few cells. Initial intracranial volumes of the recovering-like chimeras were below normal but progressively recovered to about normal by two years of age. All had normal cortical thicknesses, and none went blind. Extended neurogenesis was evident in the brains of all the chimeras.This study indicates that although CLN6 is a membrane bound protein, the consequent defect is not cell intrinsic. The lack of glial activation and inflammatory responses in the normal-like and recovering-like chimeras indicate that newly generated cells are borne into a microenvironment conducive to maturation and survival.

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Batten disease and parents: marital quality, support, and communication

Journal of the International Child Neurology Association ◽

10.17724/jicna.2017.114 ◽

2017 ◽

Author(s):

Elizabeth J Cozart ◽

Erika F Augustine ◽

Jonathan W Mink ◽

Alyssa R Thatcher ◽

Heather R Adams

Keyword(s):

Marital Quality ◽

Motor Impairment ◽

Batten Disease ◽

Premature Death ◽

Dyadic Adjustment ◽

Neuronal Ceroid Lipofuscinoses ◽

Home Nursing ◽

Parent Communication ◽

Dyadic Adjustment Scale ◽

Factors Associated

Background: The neuronal ceroid lipofuscinoses, collectively known as Batten disease, are rare pediatric neurodegenerative disorders resulting in blindness, progressive motor impairment, dementia, and premature death. This study identified services and support accessed by parents of children with Batten disease and assessed parental marital quality. Methods: Parents completed a survey to identify services their affected children received, and their own uses of social support, information, and online resources. We used the Dyadic Adjustment Scale to evaluate parental marital quality. Results: 29 parents of 23 Batten-affected children completed the survey. 18 children (78%) received receiving in-home nursing or paraprofessional care. Over 90% of parents used the internet and social media to learn or talk about Batten disease; their preferred learning method was from other parents of children with Batten disease. Batten parent marital quality was significantly lower than that reported in studies of the general population or parents of children with chronic, but non-neurodegenerative, disease. Conclusions: Parents expressed an interest in and preference for parent-to-parent communication for support and information about Batten disease. Further work is needed to understand factors associated with the significantly lower marital quality among Batten parents.

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Building a Bridge for Batten Disease

RRNMF Neuromuscular Journal ◽

10.17161/rrnmf.v2i4.15355 ◽

2021 ◽

Vol 2 (4) ◽

Author(s):

Melissa Feuerborn ◽

Carla Keirns ◽

Richard Barohn

Keyword(s):

Rare Disease ◽

Vision Loss ◽

Neurodegenerative Disorder ◽

Neuronal Ceroid Lipofuscinosis ◽

Vegetative State ◽

Batten Disease ◽

Premature Death ◽

Research Association ◽

Structured Interviews ◽

Family Conference

Background. Neuronal Ceroid Lipofuscinosis, or Batten disease, is a neurodegenerative disorder that results in seizures, vision loss, vegetative state, and premature death. This project aims to understand the value of disease organizations in the management of Batten disease progression. Methods. Seven semi-structured interviews with caregivers of children with Batten disease were conducted at a national family conference. Also, five semi-structured telephone interviews with disease organizations were conducted, two of which were Batten disease specific. Results. Most caregiver participants reported difficulties in getting a diagnosis. All participants reported significant benefit from involvement in the Batten Disease Support and Research Association (BDSRA) and associated family conference. Some of the most challenging aspects of care centered around a lack of in-home aid, medical equipment, and the education system. The disease advocacy organizations included Rare KC, the National Organization for Rare Disorders (NORD), Global Genes, Noah’s Hope, and Taylor’s Tale. Disease organizations encourage rare disease families to thrive by providing the bridge that connects patients, physicians, and researchers. A central organization implements an avenue for individuals to share information and meet people in the rare disease community. Conclusions. The participants provided clear examples of the benefits families received from being involved in a rare disease organization.

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Patient-Derived Induced Pluripotent Stem Cell Models for Phenotypic Screening in the Neuronal Ceroid Lipofuscinoses

Molecules ◽

10.3390/molecules26206235 ◽

2021 ◽

Vol 26 (20) ◽

pp. 6235

Author(s):

Ahmed Morsy ◽

Angelica V. Carmona ◽

Paul C. Trippier

Keyword(s):

Neuronal Ceroid Lipofuscinosis ◽

Batten Disease ◽

Induced Pluripotent Stem Cell ◽

Epileptic Seizures ◽

Premature Death ◽

Model Systems ◽

Neuronal Ceroid Lipofuscinoses ◽

Phenotypic Screening ◽

Lysosomal Storage ◽

Induced Pluripotent

Batten disease or neuronal ceroid lipofuscinosis (NCL) is a group of rare, fatal, inherited neurodegenerative lysosomal storage disorders. Numerous genes (CLN1–CLN8, CLN10–CLN14) were identified in which mutations can lead to NCL; however, the underlying pathophysiology remains elusive. Despite this, the NCLs share some of the same features and symptoms but vary in respect to severity and onset of symptoms by age. Some common symptoms include the progressive loss of vision, mental and motor deterioration, epileptic seizures, premature death, and in the rare adult-onset, dementia. Currently, all forms of NCL are fatal, and no curative treatments are available. Induced pluripotent stem cells (iPSCs) can differentiate into any cell type of the human body. Cells reprogrammed from a patient have the advantage of acquiring disease pathogenesis along with recapitulation of disease-associated phenotypes. They serve as practical model systems to shed new light on disease mechanisms and provide a phenotypic screening platform to enable drug discovery. Herein, we provide an overview of available iPSC models for a number of different NCLs. More specifically, we highlight findings in these models that may spur target identification and drug development.

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Natural History of Retinal Degeneration in Ovine Models of CLN5 and CLN6 Neuronal Ceroid Lipofuscinoses

10.21203/rs.3.rs-1022407/v1 ◽

2021 ◽

Author(s):

Samantha J Murray ◽

Nadia L Mitchell

Keyword(s):

Time Course ◽

Vision Loss ◽

Ganglion Cells ◽

Batten Disease ◽

Neuronal Ceroid Lipofuscinoses ◽

Optimal Timing ◽

Lysosomal Storage ◽

Retinal Layers ◽

Differential Vulnerability ◽

History Of

Abstract Neuronal ceroid lipofuscinoses (NCL; Batten disease) are a group of inherited neurodegenerative diseases with a common set of symptoms including cognitive and motor decline and vision loss. Naturally occurring sheep models of CLN5 and CLN6 disease display the key clinical features of NCL, including a progressive loss of vision. We assessed retinal histology, inflammation, and lysosomal storage accumulation in CLN5 affected (CLN5−/−) and CLN6 affected (CLN6−/−) sheep eyes and age-matched controls at 3, 6, 12, and 18 months of age to determine the onset and progression of retinal pathology in NCL sheep. The retina of CLN5−/− sheep shows progressive atrophy of the outer retinal layers, widespread inflammation, and accumulation of lysosomal storage in retinal ganglion cells late in disease. In contrast, CLN6−/− retina shows significant atrophy of all retinal layers, progressive inflammation, and earlier accumulation of lysosomal storage. This study has highlighted the differential vulnerability of retinal layers and the time course of retinal atrophy in two distinct models of NCL disease. This data will be valuable in determining potential targets for ocular therapies and the optimal timing of these therapies for protection from retinal dysfunction and degeneration in NCL.

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Neonatal brain-directed gene therapy rescues a mouse model of neurodegenerative CLN6 Batten disease

10.1101/673848 ◽

2019 ◽

Author(s):

Sophia-Martha kleine Holthaus ◽

Saul Martin-Herranz ◽

Giulia Massaro ◽

Mikel Aristorena ◽

Justin Hoke ◽

...

Keyword(s):

Gene Therapy ◽

Mouse Model ◽

Motor Coordination ◽

Transmembrane Protein ◽

Batten Disease ◽

Premature Death ◽

Neuronal Ceroid Lipofuscinoses ◽

Therapeutic Effects ◽

Lysosomal Storage ◽

Enzyme Replacement

The neuronal ceroid lipofuscinoses (NCLs), more commonly referred to as Batten disease, are a group of inherited lysosomal storage disorders that present with neurodegeneration, loss of vision and premature death. There are at least 13 genetically distinct forms of NCL. Enzyme replacement therapies and preclinical studies on gene supplementation have shown promising results for NCLs caused by lysosomal enzyme deficiencies. The development of gene therapies targeting the brain for NCLs caused by defects in transmembrane proteins has been more challenging and only limited therapeutic effects in animal models have been achieved so far. Here, we describe the development of an adeno-associated virus (AAV)-mediated gene therapy to treat the neurodegeneration in a mouse model of CLN6 disease, a form of NCL with a deficiency in the membrane-bound protein CLN6. We show that neonatal bilateral intracerebroventricular injections with AAV9 carrying CLN6 increase lifespan by more than 90%, maintain motor skills and motor coordination and reduce neuropathological hallmarks of Cln6-deficient mice up to 23 months post vector administration. These data demonstrate that brain-directed gene therapy is a valid strategy to treat the neurodegeneration of CLN6 disease and may be applied to other forms of NCL caused by transmembrane protein deficiencies in the future.

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Mitochondrial collapse links PFKFB3-promoted glycolysis with CLN7/MFSD8 neuronal ceroid lipofuscinosis pathogenesis

10.1101/2020.10.20.345314 ◽

2020 ◽

Author(s):

Irene Lopez-Fabuel ◽

Marina Garcia-Macia ◽

Costantina Buondelmonte ◽

Olga Burmistrova ◽

Nicolo Bonora ◽

...

Keyword(s):

Clinical Symptoms ◽

Neuronal Ceroid Lipofuscinosis ◽

Batten Disease ◽

Glycolytic Enzyme ◽

Neuronal Ceroid Lipofuscinoses ◽

Loss Of Function ◽

Biochemical Processes ◽

Lysosomal Accumulation ◽

Lysosomal Membrane Glycoprotein

The neuronal ceroid lipofuscinoses (NCLs) are a family of monogenic life-limiting pediatric neurodegenerative disorders collectively known as Batten disease1. Although genetically heterogeneous2, NCLs share several clinical symptoms and pathological hallmarks such as lysosomal accumulation of lipofuscin and astrogliosis2,3. CLN7 disease belongs to a group of NCLs that present in late infancy4–6 and, whereas CLN7/MFSD8 gene is known to encode a lysosomal membrane glycoprotein4,7–9, the biochemical processes affected by CLN7-loss of function are unexplored thus preventing development of potential treatments1,10. Here, we found in the Cln7Δex2 mouse model11 of CLN7 disease that failure in the autophagy-lysosomal pathway causes accumulation of structurally and bioenergetically impaired, reactive oxygen species (ROS)-producing neuronal mitochondria that contribute to CLN7 pathogenesis. Cln7Δex2 neurons exhibit a metabolic shift mediated by pro-glycolytic enzyme 6-phosphofructo-2-kinase/fructose-2,6-bisphosphatase-3 (PFKFB3). PFKFB3 inhibition in Cln7Δex2 mice in vivo and in CLN7 patients-derived cells rectified key disease hallmarks. Thus, specifically targeting glycolysis may alleviate CLN7 pathogenesis.

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Psychological Distress and Post-Traumatic Symptomatology among Dental Healthcare Workers in Russia: Results of a Pilot Study

International Journal of Environmental Research and Public Health ◽

10.3390/ijerph18020708 ◽

2021 ◽

Vol 18 (2) ◽

pp. 708 ◽

Cited By ~ 1

Author(s):

Maria Sarapultseva ◽

Alena Zolotareva ◽

Igor Kritsky ◽

Natal’ya Nasretdinova ◽

Alexey Sarapultsev

Keyword(s):

Psychological Distress ◽

Healthcare Workers ◽

Mental Health Problems ◽

Clinical Symptoms ◽

Stress Disorders ◽

Self Report ◽

Ptsd Symptoms ◽

Event Scale ◽

Post Traumatic ◽

The Impact

The spread of SARS-CoV-2 infection has increased the risk of mental health problems, including post-traumatic stress disorders (PTSD), and healthcare workers (HCWs) are at greater risk than other occupational groups. This observational cross-sectional study aimed to explore the symptoms of depression, anxiety, and PTSD among dental HCWs in Russia during the coronavirus disease 2019 (COVID-19) pandemic. The survey was carried out among 128 dental HCWs from three dental clinics of Ekaterinburg, Russia. The mean age of the sample was 38.6 years. Depression, anxiety, and stress were assessed using the Depression Anxiety and Stress Scale-21 (DASS-21); PTSD was assessed using the PTSD Symptom Scale-Self-Report (PSS-SR); subjective distress was assessed using the Impact of Event Scale-Revised (IES-R). The results indicated that 20.3–24.2% HCWs had mild to extremely severe symptoms of psychological distress, and 7.1–29.7% had clinical symptoms of PTSD. No differences between females and males were revealed. HCWs working directly with patients had significantly higher levels of PTSD symptoms and the risk of PTSD development compared to those working indirectly, whereas older HCWs had significantly higher levels of both psychological distress and PTSD symptoms compared to younger HCWs. Thus, dental HCWs are at high risk for psychological distress and PTSD symptoms during the COVID-19 pandemic.

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Ethnicity and outcomes in patients hospitalised with COVID-19 infection in East London: an observational cohort study

BMJ Open ◽

10.1136/bmjopen-2020-042140 ◽

2021 ◽

Vol 11 (1) ◽

pp. e042140

Author(s):

Vanessa J Apea ◽

Yize I Wan ◽

Rageshri Dhairyawan ◽

Zudin A Puthucheary ◽

Rupert M Pearse ◽

...

Keyword(s):

Premature Death ◽

Hospital Length ◽

Hospital Length Of Stay ◽

Organ Support ◽

Invasive Ventilation ◽

Black Patients ◽

Hospitalised Patients ◽

Observational Cohort ◽

The Impact ◽

To Receive

ObjectiveTo describe outcomes within different ethnic groups of a cohort of hospitalised patients with confirmed COVID-19 infection. To quantify and describe the impact of a number of prognostic factors, including frailty and inflammatory markers.SettingFive acute National Health Service Hospitals in east London.DesignProspectively defined observational study using registry data.Participants1737 patients aged 16 years or over admitted to hospital with confirmed COVID-19 infection between 1 January and 13 May 2020.Main outcome measuresThe primary outcome was 30-day mortality from time of first hospital admission with COVID-19 diagnosis during or prior to admission. Secondary outcomes were 90-day mortality, intensive care unit (ICU) admission, ICU and hospital length of stay and type and duration of organ support. Multivariable survival analyses were adjusted for potential confounders.Results1737 were included in our analysis of whom 511 had died by day 30 (29%). 538 (31%) were from Asian, 340 (20%) black and 707 (40%) white backgrounds. Compared with white patients, those from minority ethnic backgrounds were younger, with differing comorbidity profiles and less frailty. Asian and black patients were more likely to be admitted to ICU and to receive invasive ventilation (OR 1.54, (95% CI 1.06 to 2.23); p=0.023 and OR 1.80 (95% CI 1.20 to 2.71); p=0.005, respectively). After adjustment for age and sex, patients from Asian (HR 1.49 (95% CI 1.19 to 1.86); p<0.001) and black (HR 1.30 (95% CI 1.02 to 1.65); p=0.036) backgrounds were more likely to die. These findings persisted across a range of risk factor-adjusted analyses accounting for major comorbidities, obesity, smoking, frailty and ABO blood group.ConclusionsPatients from Asian and black backgrounds had higher mortality from COVID-19 infection despite controlling for all previously identified confounders and frailty. Higher rates of invasive ventilation indicate greater acute disease severity. Our analyses suggest that patients of Asian and black backgrounds suffered disproportionate rates of premature death from COVID-19.

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