Distinct pathogenic processes between Fig4-deficient motor and sensory neurons

Istvan Katona; Xuebao Zhang; Yunhong Bai; Michael E Shy; Jiasong Guo; Qing Yan; James Hatfield; William J Kupsky; Jun Li

doi:10.1111/j.1460-9568.2011.07651.x

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Distinct pathogenic processes between Fig4-deficient motor and sensory neurons

Journal article

Peer reviewed

Distinct pathogenic processes between Fig4-deficient motor and sensory neurons

Istvan Katona, Xuebao Zhang, Yunhong Bai, Michael E Shy, Jiasong Guo, Qing Yan, James Hatfield, William J Kupsky and Jun Li

The European journal of neuroscience, Vol.33(8), pp.1401-1410

04/2011

DOI: 10.1111/j.1460-9568.2011.07651.x

PMID: 21410794

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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.

Vacuoles - ultrastructure

Humans

Autophagy

Motor Neurons - pathology

Nerve Degeneration - metabolism

Receptor, IGF Type 2 - metabolism

Charcot-Marie-Tooth Disease - genetics

Sensory Receptor Cells - physiology

Motor Neurons - cytology

Disease Models, Animal

Motor Neurons - physiology

Flavoproteins - metabolism

Sensory Receptor Cells - pathology

Flavoproteins - genetics

Cells, Cultured

Ganglia, Spinal - ultrastructure

Mitochondria - metabolism

Charcot-Marie-Tooth Disease - pathology

Nerve Degeneration - pathology

Mice, Knockout

Animals

Proteins - metabolism

Sensory Receptor Cells - cytology

Ganglia, Spinal - pathology

Phosphoinositide Phosphatases

Vacuoles - metabolism

Mice

Lysosomal-Associated Membrane Protein 2 - metabolism

Details

Title: Subtitle: Distinct pathogenic processes between Fig4-deficient motor and sensory neurons
Creators: Istvan Katona - Department of Neurology, Wayne State University, Detroit, MI, USA
Xuebao Zhang
Yunhong Bai
Michael E Shy
Jiasong Guo
Qing Yan
James Hatfield
William J Kupsky
Jun Li
Resource Type: Journal article
Publication Details: The European journal of neuroscience, Vol.33(8), pp.1401-1410
Publisher: France
DOI: 10.1111/j.1460-9568.2011.07651.x
PMID: 21410794
ISSN: 0953-816X
eISSN: 1460-9568
Language: English
Date published: 04/2011
Academic Unit: Neurology; Molecular Physiology and Biophysics; Stead Family Department of Pediatrics; Iowa Neuroscience Institute
Record Identifier: 9984020786802771

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