Phenotypic evaluation of a childhood-onset parkinsonism-dystonia mouse model with inherent postural abnormalities

Abstract Lafora disease (LD) is a fatal childhood-onset dementia characterized by the extensive accumulation of glycogen aggregates—the so-called Lafora Bodies (LBs)—in several organs. The accumulation of LBs in the brain underlies the neurological phenotype of the disease. LBs are composed of abnormal glycogen and various associated proteins, including p62, an autophagy adaptor that participates in the aggregation and clearance of misfolded proteins. To study the role of p62 in the formation of LBs and its participation in the pathology of LD, we generated a mouse model of the disease (malinKO) lacking p62. Deletion of p62 prevented LB accumulation in skeletal muscle and cardiac tissue. In the brain, the absence of p62 altered LB morphology and increased susceptibility to epilepsy. These results demonstrate that p62 participates in the formation of LBs and suggest that the sequestration of abnormal glycogen into LBs is a protective mechanism through which it reduces the deleterious consequences of its accumulation in the brain.

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Lack of p62 impairs glycogen aggregation and exacerbates pathology in a mouse model of myoclonic epilepsy of Lafora

10.1101/2021.06.03.446965 ◽

2021 ◽

Author(s):

Pasquale Pellegrini ◽

Arnau Hervera Abad ◽

Olga Varea ◽

Mary Kathryn brewer ◽

Iliana Lopez-Soldado ◽

...

Keyword(s):

Mouse Model ◽

Cardiac Tissue ◽

Protective Mechanism ◽

Lafora Disease ◽

Childhood Onset ◽

Neurological Phenotype ◽

Associated Proteins ◽

The Brain ◽

Increased Susceptibility

Background: Lafora disease (LD) is a fatal childhood onset dementia characterized by the extensive accumulation of glycogen aggregates the so-called Lafora Bodies (LBs) in several organs. The accumulation of LBs in the brain underlies the neurological phenotype of the disease. LBs are composed of abnormal glycogen and various associated proteins, including p62, an autophagy adaptor that participates in the aggregation and clearance of misfolded proteins. Methods: To study the role of p62 in the formation of LBs and its participation in the pathology of LD, we generated a mouse model of the disease (malinKO) lacking p62. Results: Deletion of p62 prevented LB accumulation in skeletal muscle and cardiac tissue. In the brain, the absence of p62 altered LB morphology and increased susceptibility to epilepsy. Conclusions: These results demonstrate that p62 participates in the formation of LBs and suggest that the sequestration of abnormal glycogen into LBs is a protective mechanism through which to reduce the deleterious consequences of its accumulation in the brain.

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Regenerating myofibers in tibialis anterior muscles of young ‘MDX’ mice

Proceedings, annual meeting, Electron Microscopy Society of America ◽

10.1017/s0424820100127943 ◽

1987 ◽

Vol 45 ◽

pp. 726-727

Author(s):

H. D. Geissinge ◽

L.D. Rhodes

Keyword(s):

Muscular Dystrophy ◽

Mouse Model ◽

Tibialis Anterior ◽

Physiological Activity ◽

Mdx Mice ◽

Mode Of Inheritance

A recently discovered mouse model (‘mdx’) for muscular dystrophy in man may be of considerable interest, since the disease in ‘mdx’ mice is inherited by the same mode of inheritance (X-linked) as the human Duchenne (DMD) muscular dystrophy. Unlike DMD, which results in a situation in which the continual muscle destruction cannot keep up with abortive regenerative attempts of the musculature, and the sufferers of the disease die early, the disease in ‘mdx’ mice appears to be transient, and the mice do not die as a result of it. In fact, it has been reported that the severely damaged Tibialis anterior (TA) muscles of ‘mdx’ mice seem to display exceptionally good regenerative powers at 4-6 weeks, so much so, that these muscles are able to regenerate spontaneously up to their previous levels of physiological activity.

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