CMT 4J: Distinct pathogenic processes between Fig4-deficient motor and sensory n

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Eur J Neurosci. 2011 Mar 17. doi: 10.1111/j.1460-9568.2011.07651.x. [Epub ahead

of print]

Distinct pathogenic processes between Fig4-deficient motor and sensory neurons.

Katona I, Zhang X, Bai Y, Shy ME, Guo J, Yan Q, Hatfield J, Kupsky WJ, Li J.

Department of Neurology, Wayne State University, Detroit, MI, USA Department of

Neurology, Vanderbilt University, 1161 21th Avenue South, Nashville, TN 37232,

USA Department of Molecular Medicine and Genetics, Wayne State University,

Detroit, MI, USA Pathology and Laboratory Medicine Service, D. Dingell VA

Medical Center, Detroit, MI, USA Department of Pathology, Wayne State

University, Detroit, MI, USA Tennessee Valley Healthcare System - Nashville

Campus, Nashville, TN, USA.

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.