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The mouse lysosomal membrane protein 1 gene as a candidate for the motorneuron degeneration (mnd) locus
N A Bermingham1, J E Martin, E M Fisher
1Department of Biochemistry and Molecular Genetics, Imperial College of Medicine at St. Mary's, London, UK.
Abstract:
The motorneuron degeneration (mnd) mutation causes one of the few late-onset progressive neurodegenerations in mice; therefore, the mnd mouse is a valuable paradigm for studying neurodegenerative biology. The mnd mutation may also model human neuronal ceroid lipofuscinosis (NCL) or Batten disease. mnd maps to the centromeric region of mouse chromosome 8, which likely corresponds to portions of human chromosomes 13,8, or 19; we note that the chromosome 13 portion maps close to a region thought to contain the human Type V NCL locus. We have identified candidate genes for the mnd locus from human chromosomes 13,8, and 19, and we are mapping these genes in the mouse to determine their proximity to the mutated locus and to refine the comparative human-mouse map in this area. A candidate gene from human chromosome 13 is LAMP1, which encodes lysosomal membrane protein 1. We found that LAMP1 in the mouse lies within the region of the mnd mutation. Therefore, we sequenced LAMP1 cDNAs from homozygous mnd mice and unrelated wildtype C57BL/6 mice. We find no differences between the two cDNA species in the regions examined, and expression analysis shows a similar LAMP1 protein distribution in wildtype and mutant mice, suggesting that an abnormal accumulation of material within normal lysosome structures is unlikely to be the pathogenetic mechanism in the mnd mouse.
Insights
The motorneuron degeneration (mnd) mouse model, a potential model for Batten disease, shows no LAMP1 gene mutations. This suggests abnormal lysosome accumulation is unlikely the cause of mnd neurodegeneration.
Area of Science:
- Neuroscience
- Genetics
- Molecular Biology
Background:
- The motorneuron degeneration (mnd) mutation in mice causes late-onset progressive neurodegeneration, serving as a model for studying such conditions.
- The mnd mutation may also model human neuronal ceroid lipofuscinosis (NCL), also known as Batten disease.
- The mnd locus maps to mouse chromosome 8, with potential homology to human chromosomes 13, 8, and 19.
Purpose of the Study:
- To investigate the role of Lysosomal Membrane Protein 1 (LAMP1) in the mnd mouse model of neurodegeneration.
- To refine the comparative human-mouse map in the region of the mnd mutation.
- To determine if LAMP1 mutations or altered expression contribute to the pathogenesis of mnd.
Main Methods:
- Positional cloning to map the mnd mutation.
- Comparative mapping of candidate genes from human chromosomes 13, 8, and 19 in the mouse.
- Sequencing of LAMP1 cDNAs from mnd mutant and wildtype mice.
- Analysis of LAMP1 protein distribution in wildtype and mnd mice.
Main Results:
- The mouse LAMP1 gene was localized to the chromosomal region containing the mnd mutation.
- Sequencing of LAMP1 cDNAs revealed no differences between homozygous mnd mice and wildtype mice.
- LAMP1 protein expression and distribution appeared similar in both wildtype and mnd mice.
Conclusions:
- Mutations in the LAMP1 gene are unlikely to be the cause of the mnd mutation.
- Abnormal accumulation of material within normal lysosome structures is probably not the primary pathogenetic mechanism in the mnd mouse model.
- Further investigation is needed to elucidate the precise genetic cause and pathomechanism of motorneuron degeneration in the mnd mouse.