Journal
NEUROPATHOLOGY AND APPLIED NEUROBIOLOGY
Volume 47, Issue 1, Pages 73-95Publisher
WILEY
DOI: 10.1111/nan.12635
Keywords
axonal transport; microtubules; neuritogenesis; neurons; plectin; tau
Categories
Funding
- Austrian Science Research Fund (FWF) [P23729-B11, I1207-B24, P31541-B27]
- Multilocation Deutsche Forschungsgemeinschaft (DFG)-Research Unit 1228 Molecular Pathogenesis of Myofibrillar Myopathies
- Research Agency of Slovenia [P3 0310]
- EuroCellNet COST Action [CA15214]
- Austrian Science Fund (FWF) [P31541] Funding Source: Austrian Science Fund (FWF)
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P1c influences axonal microtubule dynamics through isoform-specific interaction with tubulin. Its deficiency in neurons affects microtubule dynamics, leading to altered neuritogenesis, neurite branching, growth cone morphology, and vesicles and mitochondria movement. On an organismal level, P1c deficiency results in impaired pain sensitivity, diminished learning capabilities, and reduced long-term memory in mice, indicating potential implications for cytoskeleton-related neuropathies.
Aims Plectin, a universally expressed multi-functional cytolinker protein, is crucial for intermediate filament networking, including crosstalk with actomyosin and microtubules. In addition to its involvement in a number of diseases affecting skin, skeletal muscle, heart, and other stress-exposed tissues, indications for a neuropathological role of plectin have emerged. Having identified P1c as the major isoform expressed in neural tissues in previous studies, our aim for the present work was to investigate whether, and by which mechanism(s), the targeted deletion of this isoform affects neuritogenesis and proper nerve cell functioning. Methods Forex vivophenotyping, we used dorsal root ganglion and hippocampal neurons derived from isoform P1c-deficient and plectin-null mice, complemented byin vitroexperiments using purified proteins and cell fractions. To assess the physiological significance of the phenotypic alterations observed in P1c-deficient neurons, P1c-deficient and wild-type littermate mice were subjected to standard behavioural tests. Results We demonstrate that P1c affects axonal microtubule dynamics by isoform-specific interaction with tubulin. P1c deficiency in neurons leads to altered dynamics of microtubules and excessive association with tau protein, affecting neuritogenesis, neurite branching, growth cone morphology, and translocation and directionality of movement of vesicles and mitochondria. On the organismal level, we found P1c deficiency manifesting as impaired pain sensitivity, diminished learning capabilities and reduced long-term memory of mice. Conclusions Revealing a regulatory role of plectin scaffolds in microtubule-dependent nerve cell functions, our results have potential implications for cytoskeleton-related neuropathies.
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