TY - JOUR
T1 - Distinct pathogenic processes between Fig4-deficient motor and sensory neurons
AU - Katona, Istvan
AU - Zhang, Xuebao
AU - Bai, Yunhong
AU - Shy, Michael E.
AU - Guo, Jiasong
AU - Yan, Qing
AU - Hatfield, James
AU - Kupsky, William J.
AU - Li, Jun
PY - 2011/4
Y1 - 2011/4
N2 - 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.
AB - 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.
KW - 5P
KW - CMT4J
KW - FIG4
KW - Intracellular organelle trafficking
KW - Lysosomal storage
KW - Motor neuron disease
KW - PI3
UR - http://www.scopus.com/inward/record.url?scp=79954471977&partnerID=8YFLogxK
UR - http://www.scopus.com/inward/citedby.url?scp=79954471977&partnerID=8YFLogxK
U2 - 10.1111/j.1460-9568.2011.07651.x
DO - 10.1111/j.1460-9568.2011.07651.x
M3 - Article
C2 - 21410794
AN - SCOPUS:79954471977
VL - 33
SP - 1401
EP - 1410
JO - European Journal of Neuroscience
JF - European Journal of Neuroscience
SN - 0953-816X
IS - 8
ER -