Abstract
Mutations of FIG4 are responsible for Yunis-Varón syndrome, familial epilepsy with polymicrogyria, and Charcot-Marie-Tooth type 4J neuropathy (CMT4J). Although loss of the FIG4 phospholipid phosphatase consistently causes decreased PtdIns(3,5)P2 levels, cell-specific sensitivity to partial loss of FIG4 function may differentiate FIG4-associated disorders. CMT4J is an autosomal recessive neuropathy characterized by severe demyelination and axonal loss in human, with both motor and sensory involvement. However, it is unclear whether FIG4 has cell autonomous roles in both motor neurons and Schwann cells, and how loss of FIG4/PtdIns(3,5)P2-mediated functions contribute to the pathogenesis of CMT4J. Here, we report that mice with conditional inactivation of Fig4 in motor neurons display neuronal and axonal degeneration. In contrast, conditional inactivation of Fig4 in Schwann cells causes demyelination and defects in autophagy-mediated degradation. Moreover, Fig4-regulated endolysosomal trafficking in Schwann cells is essential for myelin biogenesis during development and for proper regeneration/remyelination after injury. Our data suggest that impaired endolysosomal trafficking in both motor neurons and Schwann cells contributes to CMT4J neuropathy.
Highlights
In yeast and mammalian cells, the Fig4/FIG4 phospholipid phosphatase controls the generation and turnover of the PtdIns[3,5]P2 phosphoinositide, a regulator of membrane and protein trafficking at the level of the endosome – lysosome axis
Our data suggest that impaired endolysosomal trafficking in both motor neurons and Schwann cells contributes to Charcot-Marie-Tooth type 4J neuropathy (CMT4J) neuropathy
CMT4J patients initially display a prevalent motor and asymmetric neuropathy, which is a typical feature of a lower motor neuron disease rather than of demyelinating CMT neuropathies [6,7]
Summary
In yeast and mammalian cells, the Fig4/FIG4 phospholipid phosphatase controls the generation and turnover of the PtdIns[3,5]P2 phosphoinositide, a regulator of membrane and protein trafficking at the level of the endosome – lysosome axis. Yunis-Varon syndrome is a severe disorder with autosomal recessive inheritance characterised by skeletal and structural brain abnormalities and facial dysmorphism [5]. A homozygous missense mutation causing partial loss of FIG4 function was demonstrated to co-segregate with polymicrogyria, psychiatric manifestations and epilepsy in a consanguineous Moroccan family, suggesting a role for FIG4 in the regulation of cortical brain development [10]. ALS is a severe neurological disorder characterized by selective neurodegeneration of lower
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