Mid1 is associated with androgen-dependent axonal vulnerability of motor neurons in spinal and bulbar muscular atrophy.

Abstract

Spinal and bulbar muscular atrophy (SBMA) is an adult-onset hereditary neurodegenerative disease caused by the expansions of CAG repeats in the androgen receptor (AR) gene. Androgen-dependent nuclear accumulation of pathogenic AR protein causes degeneration of lower motor neurons, leading to progressive muscle weakness and atrophy. While the successful induction of SBMA-like pathology has been achieved in mouse models, mechanisms underlying motor neuron vulnerability remain unclear. In the present study, we performed a transcriptome-based screening for genes expressed exclusively in motor neurons and dysregulated in the spinal cord of SBMA mice. We found upregulation of Mid1 encoding a microtubule-associated RNA binding protein which facilitates the translation of CAG-expanded mRNAs. Based on the finding that lower motor neurons begin expressing Mid1 during embryonic stages, we developed an organotypic slice culture system of the spinal cord obtained from SBMA mouse fetuses to study the pathogenic role of Mid1 in SBMA motor neurons. Impairment of axonal regeneration arose in the spinal cord culture in SBMA mice in an androgen-dependent manner, but not in mice with non-CAG-expanded AR, and was either exacerbated or ameliorated by Mid1 overexpression or knockdown, respectively. Hence, an early Mid1 expression confers vulnerability to motor neurons, at least by inducing axonogenesis defects, in SBMA.

• Authors: Yosuke Ogura, Kentaro Sahashi, Tomoki Hirunagi, Madoka Iida, Takaki Miyata, Masahisa Katsuno
• Journal: Cell death & disease (Cell Death Dis) Vol. 13 Issue 7 Pg. 601 (07 13 2022) ISSN: 2041-4889 [Electronic] England
• PMID: 35821212 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)
• Copyright: © 2022. The Author(s).

Chemical References

• Androgens
• Mid1 protein, mouse
• Ubiquitin-Protein Ligases

Topics

• Androgens (metabolism, pharmacology)
• Animals
• Bulbo-Spinal Atrophy, X-Linked (metabolism, pathology)
• Mice
• Motor Neurons (metabolism, pathology)
• Muscular Atrophy (metabolism)
• Neurodegenerative Diseases (metabolism)
• Ubiquitin-Protein Ligases (metabolism)