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Targeted disruption of the Cln3 gene provides a mouse model for Batten disease. The Batten Mouse Model Consortium
H M Mitchison1, D J Bernard, N D Greene
1Royal Free and University College London Medical School, Rayne Institute, University Street, London, WC1E 6JJ, United Kingdom.
Abstract:
Batten disease, a degenerative neurological disorder with juvenile onset, is the most common form of the neuronal ceroid lipofuscinoses. Mutations in the CLN3 gene cause Batten disease. To facilitate studies of Batten disease pathogenesis and treatment, a murine model was created by targeted disruption of the Cln3 gene. Mice homozygous for the disrupted Cln3 allele had a neuronal storage disorder resembling that seen in Batten disease patients: there was widespread and progressive intracellular accumulation of autofluorescent material that by EM displayed a multilamellar rectilinear/fingerprint appearance. Inclusions contained subunit c of mitochondrial ATP synthase. Mutant animals also showed neuropathological abnormalities with loss of certain cortical interneurons and hypertrophy of many interneuron populations in the hippocampus. Finally, as is true in Batten disease patients, there was increased activity in the brain of the lysosomal protease Cln2/TPP-1. Our findings are evidence that the Cln3-deficient mouse provides a valuable model for studying Batten disease.
Insights
Researchers developed a Cln3 gene-deficient mouse model for Batten disease, a rare neurological disorder. This model exhibits key pathological features, aiding in studying the disease and potential treatments.
Area of Science:
- Neuroscience
- Genetics
- Cell Biology
Background:
- Batten disease is a rare, inherited neurodegenerative disorder.
- It is the most common form of neuronal ceroid lipofuscinoses.
- Mutations in the CLN3 gene are the primary cause of Batten disease.
Purpose of the Study:
- To create a murine model for Batten disease research.
- To investigate Batten disease pathogenesis and test potential treatments.
- To validate the Cln3-deficient mouse as a model for human disease.
Main Methods:
- Targeted disruption of the Cln3 gene in mice.
- Electron microscopy (EM) to analyze intracellular material.
- Neuropathological examination of mouse brains.
- Biochemical analysis of lysosomal enzyme activity.
Main Results:
- Cln3-deficient mice exhibited a neuronal storage disorder mirroring human Batten disease.
- Widespread accumulation of autofluorescent material with fingerprint-like structures was observed.
- Mitochondrial ATP synthase subunit c was identified within cellular inclusions.
- Neuropathological changes included interneuron loss and hypertrophy.
- Increased brain activity of lysosomal protease Cln2/TPP-1 was noted.
Conclusions:
- The Cln3-deficient mouse serves as a valuable preclinical model for Batten disease.
- This model facilitates the study of disease mechanisms.
- It offers a platform for evaluating therapeutic interventions for Batten disease.
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