Distinct pathogenic processes between Fig4-deficient motor and sensory neurons

Area of Science:

• Neuroscience
• Genetics
• Cell Biology

Background:

• Loss of function in the FIG4 gene is linked to Charcot-Marie-Tooth disease (CMT)-4J, exhibiting symptoms similar to motor neuron disease (MND).
• The precise mechanisms driving neurodegeneration in FIG4-related disorders remain largely unknown.

Purpose of the Study:

• To investigate the cellular and molecular mechanisms underlying neurodegeneration in Fig4-deficient pale tremor (plt) mice, a model for CMT4J.
• To differentiate the pathological changes in sensory and motor neurons.

Main Methods:

• Utilized ultrastructural studies on dorsal root ganglion (DRG) sensory neurons and spinal motor neurons from plt mice.
• Analyzed the accumulation of specific cellular organelles and protein levels (LAMP2, NPC1, mannose-6-phosphate receptor).

Main Results:

• Vacuoles with membrane disruption were observed in DRG sensory neurons of plt mice as early as postnatal day 4.
• Spinal motor neurons, conversely, showed accumulation of electron-dense organelles resembling those in lysosomal storage disorders, not vacuoles.
• Lysosomal protein levels (LAMP2, NPC1) were elevated in motor neurons, indicating altered lysosomal function.

Conclusions:

• Fig4 deficiency differentially impacts motor and sensory neurons, leading to distinct pathological alterations.
• Mechanisms may involve excessive lysosomal molecule retention or vacuolated organelle disruption in motor neurons.
• These distinct cellular changes likely contribute to the observed neurodegeneration in CMT4J and MND.