Deletion or alteration of this motif induced trafficking impairment in both in vitro systems and animal models, the latter one accompanied by photoreceptor cell death, displaying its very important role for transport to the membranous rod outer segment (ROS) [14] [16].
Mitochondrial trafficking impairment could occur secondarily to mitochondrial defects.
Demyelination in these models can be the consequence of a general endolysosomal trafficking impairment and loss of LE/LY homeostasis.
Both mutated CADM1 and neuroligin 3 R451C) induced upregulation of C/EBP-homologous protein (CHOP), an ER stress marker, suggesting that in addition to the trafficking impairment, this CHOP upregulation may also be involved in ASD pathogenesis.
We found that Fig4 loss in motor neurons causes neuronal and axonal degeneration, whereas the Fig4-Schwann conditionalional mutant displays a general trafficking impairment, leading to a defect in autophagy-mediated degradation and demyelination.
Since specific loss of Fig4 in Schwann cells appears to cause an endolysosomal trafficking impairment, we asked whether the altered regeneration of myelinated fibres could be caused by delayed clearance of myelin debris by Schwann cells.
The paper also highlights the current knowledge of the structural and interaction specificities of BICD2 protein affected by the described missense mutations and supports dynein-dynactin trafficking impairment as a common pathomechanism (Oates et al., 2013).
Consistent with this, we also report that Fig4 conditional mutants in Schwann cells (Fig4 Floxed/Floxed, P0-Cre and Fig4 Floxed/ plt, P0-Cre mice) exhibit accumulation of vesicles and organelles in the cytosol of myelinating cells indicative of a general trafficking impairment of the endolysosome axis, as well as enlargement of LE/LY and a block in autophagy.
Morphological analysis of sciatic nerve revealed an accumulation of organelles and of lipidic material/vesicles in the cytoplasm of myelinating Schwann cells in Fig4 Floxed/Floxed, P0-Cre nerve fibres at P30, P60 and 4 months of age, suggesting a general trafficking impairment (Fig. 2F and H and Fig. 3B).
As an intracellular pathogen, Francisella is known to modulate intracellular trafficking, including impairment of phagosome maturation and disrupting the vesicle membrane to escape into cytosol [ 31].
