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Distinct pathogenic processes between Fig4‐deficient motor and sensory neurons
Author(s) -
Katona Istvan,
Zhang Xuebao,
Bai Yunhong,
Shy Michael E.,
Guo Jiasong,
Yan Qing,
Hatfield James,
Kupsky William J.,
Li Jun
Publication year - 2011
Publication title -
european journal of neuroscience
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.346
H-Index - 206
eISSN - 1460-9568
pISSN - 0953-816X
DOI - 10.1111/j.1460-9568.2011.07651.x
Subject(s) - vacuole , biology , endosome , sensory neuron , motor neuron , dorsal root ganglion , sensory system , neurodegeneration , neuroscience , neuron , axoplasmic transport , microbiology and biotechnology , amyotrophic lateral sclerosis , organelle , receptor , spinal cord , pathology , cytoplasm , biochemistry , medicine , disease
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.