myelin-basic-protein and Spinocerebellar-Ataxias

Spinocerebellar ataxia type 1 (SCA1) is a devastating neurodegenerative disorder in which an abnormally expanded polyglutamine tract is inserted into causative ataxin-1 proteins. We have previously shown that SCA1 knockin (SCA1-KI) mice over 6 months of age exhibit a degeneration of motor neuron axons and their encasing myelin sheaths, as reported in SCA1 patients. We examined whether axon degeneration precedes myelin degeneration or vice versa in SCA1-KI mice and then attempted to mitigate motor neuron degeneration by intrathecally administering mesenchymal stem cells (MSCs). Temporal examination of the diameters of motor neuron axons and their myelin sheaths revealed a decrease in diameter of the axon but not of the myelin sheaths in SCA1-KI mice as early as 1 month of age, which suggests secondary degeneration of the myelin sheaths. We injected MSCs into the intrathecal space of SCA1-KI mice at 1 month of age, which resulted in a significant suppression of degeneration of both motor neuron axons and myelin sheaths, even 6 months after the MSC injection. Thus, MSCs effectively suppressed peripheral nervous system degeneration in SCA1-KI mice. It has not yet been clarified how clinically administered MSCs exhibit significant therapeutic effects in patients with SCA1. The morphological evidence presented in this current mouse study might explain the mechanisms that underlie the therapeutic effects of MSCs that are observed in patients with SCA1.

Topics: Analysis of Variance; Animals; Ataxin-1; Cell- and Tissue-Based Therapy; Disease Models, Animal; Gene Expression Regulation; Green Fluorescent Proteins; Humans; Mesenchymal Stem Cells; Mice; Mice, Inbred C57BL; Mice, Transgenic; Motor Neurons; Myelin Basic Protein; Nerve Degeneration; Spinal Cord; Spinocerebellar Ataxias; Time Factors

Spinocerebellar ataxia type 1 (SCA1) is caused by the ataxin-1 protein (ATXN1) with an abnormally expanded polyglutamine tract and is characterized by progressive neurodegeneration. We previously showed that intrathecal injection of mesenchymal stem cells (MSCs) during the nonsymptomatic stage mitigates the degeneration of the peripheral nervous system (PNS) neurons in SCA1-knock-in (SCA1-KI) mice. We tested in this study whether the therapeutic effects of MSCs in SCA1-KI mice could be reproduced with MSC-releasing factor(s).. To test the effects of MSC-releasing factor(s), we used MSC-conditioned medium (MSC-CM). MSC-CM was intrathecally and/or intravenously injected into young SCA1-KI mice, and the therapeutic effects were assessed in the PNS at later ages using immunostaining, electrophysiology, and behavioral tests.. MSC-CM attenuated the degeneration of axons and myelin of spinal motor neurons. Consequently, the injected SCA1-KI mice exhibited smaller reductions in nerve conduction velocity in spinal motor neurons and reduced motor incoordination than the untreated mice.. These results suggest that factors released from MSC mitigate the morphological and functional abnormalities in the PNS that are observed in SCA1-KI mice in a paracrine manner.

Topics: Age Factors; Animals; Ataxin-1; Axons; Cells, Cultured; Culture Media, Conditioned; Disease Models, Animal; Evoked Potentials, Motor; Humans; Mesenchymal Stem Cells; Mice; Mice, Inbred C57BL; Mice, Transgenic; Motor Activity; Motor Neurons; Myelin Basic Protein; Nerve Degeneration; Reaction Time; Spinocerebellar Ataxias; Tubulin