Targeting the prodromal stage of spinocerebellar ataxia type 17 mice: G-CSF in the prevention of motor deficits via upregulating chaperone and autophagy levels.

Abstract

Spinocerebellar ataxia type 17 (SCA17), an autosomal dominant cerebellar ataxia, is a devastating, incurable disease caused by the polyglutamine (polyQ) expansion of transcription factor TATA binding protein (TBP). The polyQ expansion causes misfolding and aggregation of the mutant TBP, further leading to cytotoxicity and cell death. The well-recognized prodromal phase in many forms of neurodegeneration suggests a prolonged period of partial neuronal dysfunction prior to cell loss that may be amenable to therapeutic intervention. The objective of this study was to assess the effects and molecular mechanisms of granulocyte-colony stimulating factor (G-CSF) therapy during the pre-symptomatic stage in SCA17 mice. Treatment with G-CSF at the pre-symptomatic stage improved the motor coordination of SCA17 mice and reduced the cell loss, insoluble mutant TBP protein, and vacuole formation in the Purkinje neurons of these mice. The neuroprotective effects of G-CSF may be produced by increases in Hsp70, Beclin-1, LC3-II and the p-ERK survival pathway. Upregulation of chaperone and autophagy levels further enhances the clearance of mutant protein aggregation, slowing the progression of pathology in SCA17 mice. Therefore, we showed that the early intervention of G-CSF has a neuroprotective effect, delaying the progression of SCA17 in mutant mice via increases in the levels of chaperone expression and autophagy.

• Authors: Ya-Chin Chang, Chia-Wei Lin, Chen-Ming Hsu, Guey-Jen Lee-Chen, Ming-Tsan Su, Long-Sun Ro, Chiung-Mei Chen, Hei-Jen Huang, Hsiu Mei Hsieh-Li
• Journal: Brain research (Brain Res) Vol. 1639 Pg. 132-48 (05 15 2016) ISSN: 1872-6240 [Electronic] Netherlands
• PMID: 26972528 (Publication Type: Journal Article)
• Copyright: Copyright © 2016 Elsevier B.V. All rights reserved.

Chemical References

• HSP70 Heat-Shock Proteins
• Map1lc3b protein, mouse
• Microtubule-Associated Proteins
• Neuroprotective Agents
• Granulocyte Colony-Stimulating Factor
• Extracellular Signal-Regulated MAP Kinases

Topics

• Animals
• Apoptosis (drug effects, physiology)
• Autophagy (drug effects, physiology)
• Disease Models, Animal
• Drug Evaluation, Preclinical
• Extracellular Signal-Regulated MAP Kinases (metabolism)
• Granulocyte Colony-Stimulating Factor (pharmacology)
• HSP70 Heat-Shock Proteins (metabolism)
• Mice, Transgenic
• Microtubule-Associated Proteins (metabolism)
• Motor Activity (drug effects, physiology)
• Neuroprotective Agents (pharmacology)
• Prodromal Symptoms
• Purkinje Cells (drug effects, pathology, physiology)
• Spinocerebellar Ataxias (drug therapy, pathology, physiopathology)