title: Distinct pathogenic processes between Fig4-deficient motor and sensory neurons.
abstract: Loss of function of the FIG4 gene causes Charcot-Marie-Tooth disease (CMT)-4J with many features also found in motor neuron disease (MND). Mechanisms for the degeneration are unknown. We investigated this using Fig4-deficient pale tremor (plt) mice, a mouse model of CMT4J. Ultrastructural studies in sensory neurons of dorsal root ganglion (DRG) confirmed abundant vacuoles with membrane disruption. The vacuoles became detectable as early as postnatal day 4 in the DRG. However, the vacuoles were absent or minimal in the spinal motor neurons or cortical neurons in 2- to 5-week-old plt mice. Instead, a large number of electron-dense organelles, reminiscent of those in lysosomal storage disorders, accumulated in the motor neurons, but not in the sensory neurons of DRG. This accumulation was associated with increased levels of lysosomal proteins, such as LAMP2 and NPC1, but not mannose-6-phosphate receptor, an endosomal protein that is usually excluded from the lysosomes. Our results suggest that Fig4 deficiency affects motor neurons differently from sensory neurons by mechanisms involving excessive retention of molecules in lysosomes or disruption of vacuolated organelles. These two distinct pathological changes may contribute to neuronal degeneration.
authors.affiliation: Department of Neurology, Wayne State University, Detroit, MI, USA.
authors.forename: Istvan
authors.initials: I
authors.lastname: Katona
authors.forename: Xuebao
authors.initials: X
authors.lastname: Zhang
authors.forename: Yunhong
authors.initials: Y
authors.lastname: Bai
authors.forename: Michael E
authors.initials: ME
authors.lastname: Shy
authors.forename: Jiasong
authors.initials: J
authors.lastname: Guo
authors.forename: Qing
authors.initials: Q
authors.lastname: Yan
authors.forename: James
authors.initials: J
authors.lastname: Hatfield
authors.forename: William J
authors.initials: WJ
authors.lastname: Kupsky
authors.forename: Jun
authors.initials: J
authors.lastname: Li
mesh_terms: D000818:Animals; D001343:Autophagy; D002478:Cells, Cultured; D002607:Charcot-Marie-Tooth Disease / Q000235:genetics / Q000473:pathology; D004195:Disease Models, Animal; D005420:Flavoproteins / Q000235:genetics / Q000378:metabolism*; D005727:Ganglia, Spinal / Q000473:pathology / Q000648:ultrastructure; D006801:Humans; D047908:Intracellular Signaling Peptides and Proteins; D052119:Lysosomal-Associated Membrane Protein 2 / Q000378:metabolism; D051379:Mice; D018345:Mice, Knockout; D008928:Mitochondria / Q000378:metabolism; D009046:Motor Neurons / Q000166:cytology / Q000473:pathology* / Q000502:physiology*; D009410:Nerve Degeneration / Q000378:metabolism / Q000473:pathology; D000077296:Niemann-Pick C1 Protein; D000072180:Phosphoinositide Phosphatases; D011506:Proteins / Q000378:metabolism; D017527:Receptor, IGF Type 2 / Q000378:metabolism; D011984:Sensory Receptor Cells / Q000166:cytology / Q000473:pathology* / Q000502:physiology*; D014617:Vacuoles / Q000378:metabolism / Q000648:ultrastructure
chemical_list: D005420:Flavoproteins; D047908:Intracellular Signaling Peptides and Proteins; D052119:Lysosomal-Associated Membrane Protein 2; D000077296:Niemann-Pick C1 Protein; C106831:Npc1 protein, mouse; D011506:Proteins; D017527:Receptor, IGF Type 2; C522216:Fig4 protein, mouse; D000072180:Phosphoinositide Phosphatases