Sex bias and omission exists in Batten disease research: Systematic review of the use of animal disease models

Batten disease, also known as the neuronal ceroid lipofuscinoses (NCL), is a group of inherited neurodegenerative disorders mainly affecting children. NCL are characterised by seizures, loss of vision, and progressive motor and cognitive decline, and are the most common form of childhood dementia. At least one type of Batten disease and three types of mouse disease models show sex differences in their severity and progression. Scientific research has a recognised prevalent omission of female animals when using model organisms for basic and preclinical research. Sex bias and omission in research using animal models of Batten disease may affect understanding and treatment development. We conducted a systematic review of research publications since the first identification of NCL genes in 1995, identifying those using animal models. We found that <10 % of these papers considered sex as a biological variable. There was consistent omission of female model organisms in studies. This varied over the period but is improving; one third of papers considered sex as a biological variable in the last decade, and there is a noticeable increase in the last 5 years. The wide-ranging reasons for this published sex bias are discussed, including misunderstanding regarding oestrogen, impact on sample size, and the underrepresentation of female scientists. Their implications for Batten disease and future research are considered. Recommendations going forward support requirements by funders for consideration of sex in all stages of experimental design and implementation, and a role for publishers, families and others with a particular interest in Batten disease

btn1, the Schizosaccharomyces pombe homologue of the human Batten disease gene CLN3, regulates vacuole homeostasis

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Mutation of the parkinsonism gene ATP13A2 causes neuronal ceroid-lipofuscinosis

Neuronal ceroid lipofuscinoses (NCLs) comprise a heterogeneous group of metabolic storage diseases that present with the accumulation of autofluorescent lipopigment, neurodegeneration and premature death. Nine genes have been thus far identified as the cause of different types of NCL, with ages at onset ranging from around birth to adult, although the underlying etiology of the disease still remains elusive. We present a family with typical NCL pathology in which we performed exome sequencing and identified a single homozygous mutation in ATP13A2 that fully segregates with disease within the family. Mutations in ATP13A2 are a known cause of Kufor–Rakeb syndrome (KRS), a rare parkinsonian phenotype with juvenile onset. These data show that NCL and KRS may share etiological features and implicate the lysosomal pathway in Parkinson's disease

A central role for TOR signalling in a yeast model for juvenile CLN3 disease

Yeasts provide an excellent genetically tractable eukaryotic system for investigating the function of genes in their biological context, and are especially relevant for those conserved genes that cause disease. We study the role of btn1, the orthologue of a human gene that underlies an early onset neurodegenerative disease (juvenile CLN3 disease, neuronal ceroid lipofuscinosis (NCLs) or Batten disease) in the fission yeast Schizosaccharomyces pombe. A global screen for genetic interactions with btn1 highlighted a conserved key signalling hub in which multiple components functionally relate to this conserved disease gene. This signalling hub includes two major mitogen-activated protein kinase (MAPK) cascades, and centers on the Tor kinase complexes TORC1 and TORC2. We confirmed that yeast cells modelling CLN3 disease exhibit features consistent with dysfunction in the TORC pathways, and showed that modulating TORC function leads to a comprehensive rescue of defects in this yeast disease model. The same pathways may be novel targets in the development of therapies for the NCLs and related diseases

Research Report Rural family businesses and exporting behaviour

Driven by the importance of exporting for growth, this report examines the exporting behaviour of UK small firms in rural and urban locations. Analysing data from five waves of the Longitudinal Small Business Survey from 2015 to 2019, the report examines the development by firms of goods or services that are suitable for exporting and the subsequent decision to export, either consistently or intermittently. Overall, we find significant differences between rural and urban firms in terms of exporting, where firms located in sparse, dispersed areas were more likely to export, although less likely if they declared themselves as family businesses. We also find that some types of firms, BAME- owned and women-owned businesses, are much less likely to develop tradeable goods and services. We demonstrate how the role of advice seems specifically connected to the decision to develop tradeable goods and services, rather than exporting per se. The research confirms the importance of productivity and innovation on both exporting and developing tradeable goods and services. We propose a future research agenda on the exporting practices of rural family businesses and women-owned enterprise, and on the role of exporting advice

Rural family businesses and exporting behaviour

Driven by the importance of exporting for growth, this report examines the exporting behaviour of UK small firms in rural and urban locations. Analysing data from five waves of the Longitudinal Small Business Survey from 2015 to 2019, the report examines the development by firms of goods or services that are suitable for exporting and the subsequent decision to export, either consistently or intermittently. Overall, we find significant differences between rural and urban firms in terms of exporting, where firms located in sparse, dispersed areas were more likely to export, although less likely if they declared themselves as family businesses. We also find that some types of firms, BAMEowned and women-owned businesses, are much less likely to develop tradeable goods and services. We demonstrate how the role of advice seems specifically connected to the decision to develop tradeable goods and services, rather than exporting per se. The research confirms the importance of productivity and innovation on both exporting and developing tradeable goods and services. We propose a future research agenda on the exporting practices of rural family businesses and women-owned enterprise, and on the role of exporting advice

The Chihuahua dog: A new animal model for neuronal ceroid lipofuscinosis CLN7 disease?

Neuronal ceroid lipofuscinoses (NCLs) are a group of incurable lysosomal storage disorders characterized by neurodegeneration and accumulation of lipopigments mainly within the neurons. We studied two littermate Chihuahua dogs presenting with progressive signs of blindness, ataxia, pacing, and cognitive impairment from 1 year of age. Because of worsening of clinical signs, both dogs were euthanized at about 2 years of age. Postmortem examination revealed marked accumulation of autofluorescent intracellular inclusions within the brain, characteristic of NCL. Whole-genome sequencing was performed on one of the affected dogs. After sequence alignment and variant calling against the canine reference genome, variants were identified in the coding region or splicing regions of four previously known NCL genes (CLN6, ARSG, CLN2 [=TPP1], and CLN7 [=MFSD8]). Subsequent segregation analysis within the family (two affected dogs, both parents, and three relatives) identified MFSD8:p.Phe282Leufs13*, which had previously been identified in one Chinese crested dog with no available ancestries, as the causal mutation. Because of the similarities of the clinical signs and histopathological changes with the human form of the disease, we propose that the Chihuahua dog could be a good animal model of CLN7 disease

CLN6 disease caused by the same mutation originating in Pakistan has varying pathology

AbstractThe neuronal ceroid lipofuscinoses (NCLs), the most common neurodegenerative diseases in children, are characterised by storage of autofluorescent material that has a characteristic ultrastructure. We report two families with variant late infantile NCL, both originating from Pakistan. Probands from both families were homozygous for the same mutation (c.316dupC) but had variable pathology to that currently thought to be typical for CLN6 disease, late infantile variant. The observed pathology of one proband resembled condensed fingerprints, previously described in late infantile CLN7 and CLN8 diseases, and pathology from the second proband was thought to be absent even after repeated skin biopsy, but observed after review. This mutation is the most common NCL mutation in families originating from Pakistan and could be prioritised for testing. Finally, this report contains the first prenatal diagnosis for late infantile CLN6 disease, initially made on the basis of EM and now confirmed by mutation analysis

A central role for TOR signalling in a yeast model for juvenile CLN3 disease

Yeasts provide an excellent genetically tractable eukaryotic system for investigating the function of genes in their biological context, and are especially relevant for those conserved genes that cause disease. We study the role of btn1, the orthologue of a human gene that underlies an early onset neurodegenerative disease (juvenile CLN3 disease, neuronal ceroid lipofuscinosis (NCLs) or Batten disease) in the fission yeast Schizosaccharomyces pombe. A global screen for genetic interactions with btn1 highlighted a conserved key signalling hub in which multiple components functionally relate to this conserved disease gene. This signalling hub includes two major mitogen-activated protein kinase (MAPK) cascades, and centers on the Tor kinase complexes TORC1 and TORC2. We confirmed that yeast cells modelling CLN3 disease exhibit features consistent with dysfunction in the TORC pathways, and showed that modulating TORC function leads to a comprehensive rescue of defects in this yeast disease model. The same pathways may be novel targets in the development of therapies for the NCLs and related diseases