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Heterozygous peripheral myelin protein 22-deficient mice are affected by a progressive demyelinating tomaculous
K Adlkofer1, R Frei, D H Neuberg
1Institute of Cell Biology, Department of Biology, Swiss Federal Institute of Technology, CH-8093 Zürich, Switzerland.
Abstract:
Hereditary neuropathy with liability to pressure palsy (HNPP) is associated with a heterozygous 1.5 megabase deletion on chromosome 17 that includes the peripheral myelin protein (PMP) gene PMP22. We show that heterozygous PMP22 knock-out mice, which carry only one functional pmp22 allele and thus genetically mimic HNPP closely, display similar morphological and electrophysiological features as observed in HNPP nerves. As reported previously, focal hypermyelinating structures called tomacula, the pathological hallmarks of HNPP, develop progressively in young PMP22(+/0) mice. By following the fate of tomacula during aging, we demonstrate now that these mutant animals are also interesting models for examining HNPP disease mechanisms. Subtle electrophysiological abnormalities are detected in PMP22(+/0) mice >1 year old, and a significant number of abnormally swollen and degenerating tomacula are present. Thinly myelinated axons and supernumerary Schwann cells forming onion bulbs as fingerprints of repeated cycles of demyelination and remyelination are also encountered frequently. Quantitative analyses using electron microscopy on cross sections and light microscopy on single teased nerve fibers suggest that tomacula are intrinsically unstable structures that are prone to degeneration; however, the severity of morphological and electrophysiological abnormalities in PMP22(+/0) mice is variable. These combined findings are reminiscent of the disease progression in HNPP and offer a possible explanation about why some HNPP patients develop a chronic motor and sensory neuropathy later in life that resembles demyelinating forms of Charcot-Marie-Tooth disease by both morphological and clinical criteria.
Insights
Hereditary neuropathy with liability to pressure palsy (HNPP) mouse models reveal progressive tomacula degeneration and variable nerve abnormalities. These findings offer insights into HNPP disease progression and chronic neuropathy development.
Area of Science:
- Neuroscience
- Genetics
- Pathology
Background:
- Hereditary neuropathy with liability to pressure palsy (HNPP) is linked to a chromosome 17 deletion encompassing the PMP22 gene.
- HNPP is characterized by tomacula, focal hypermyelinating structures in peripheral nerves.
Purpose of the Study:
- To investigate the aging process and disease mechanisms in a mouse model genetically mimicking HNPP.
- To analyze the long-term morphological and electrophysiological changes in PMP22(+/0) mice.
Main Methods:
- Utilized heterozygous PMP22 knock-out (PMP22(+/0)) mice as a model for HNPP.
- Performed morphological analysis using electron and light microscopy on nerve fibers.
- Conducted electrophysiological assessments to evaluate nerve function over time.
Main Results:
- PMP22(+/0) mice exhibited progressive development and degeneration of tomacula.
- Older mice (>1 year) showed subtle electrophysiological abnormalities and frequent tomacula degeneration.
- Evidence of repeated demyelination/remyelination cycles, including thinly myelinated axons and onion bulbs, was observed.
Conclusions:
- Tomacula are intrinsically unstable and prone to degeneration in HNPP models.
- The variability in abnormalities in PMP22(+/0) mice mirrors HNPP disease progression.
- This model aids in understanding the development of chronic neuropathy in some HNPP patients, resembling demyelinating Charcot-Marie-Tooth disease.