Abstract
Spinal bulbar muscular atrophy (SBMA) is an adult-onset, slowly progressive motor neuron disease caused by abnormal CAG repeat expansion in the androgen receptor (AR) gene. Although ligand (testosterone)-dependent mutant AR aggregation has been shown to play important roles in motor neuronal degeneration by the analyses of transgenic mice models and in vitro cell culture models, the underlying disease mechanisms remain to be fully elucidated because of the discrepancy between model mice and SBMA patients. Thus, novel human disease models that recapitulate SBMA patients’ pathology more accurately are required for more precise pathophysiological analysis and the development of novel therapeutics. Here, we established disease specific iPSCs from four SBMA patients, and differentiated them into spinal motor neurons. To investigate motor neuron specific pathology, we purified iPSC-derived motor neurons using flow cytometry and cell sorting based on the motor neuron specific reporter, HB9e438::Venus, and proceeded to the genome-wide transcriptome analysis by RNA sequences. The results revealed the involvement of the pathology associated with synapses, epigenetics, and endoplasmic reticulum (ER) in SBMA. Notably, we demonstrated the involvement of the neuromuscular synapse via significant upregulation of Synaptotagmin, R-Spondin2 (RSPO2), and WNT ligands in motor neurons derived from SBMA patients, which are known to be associated with neuromuscular junction (NMJ) formation and acetylcholine receptor (AChR) clustering. These aberrant gene expression in neuromuscular synapses might represent a novel therapeutic target for SBMA.
Highlights
Spinal bulbar muscular atrophy (SBMA) is an adultonset slowly progressive lower motor neuron (MN) disease caused by abnormal CAG repeat expansion in the androgen receptor (AR) gene
The expressions of OCT4 and NANOG were confirmed by quantitative RTPCR, which showed comparable expression to KhES1 [22] in all the clones examined (Fig. 1b)
Stability of CAG repeat numbers in SBMA disease specific Induced pluripotent stem cell (iPSC) Some of the triplet repeat diseases exhibit trinucleotide repeat instability, which results in the increase of repeat numbers, earlier disease onset, and increased severity of the disease in successive generations, known as anticipation
Summary
Spinal bulbar muscular atrophy (SBMA) is an adultonset slowly progressive lower motor neuron (MN) disease caused by abnormal CAG repeat expansion in the androgen receptor (AR) gene. SBMA is characterized by weakness and atrophy of limbs and bulbar muscles caused by the degeneration of spinal and bulbar MNs [1,2,3]. The number of CAG repeat required for the Onodera et al Molecular Brain (2020) 13:18 onset of the disease is 38 or more in patients [6, 7], but more than 90 in transgenic mice models [8]. The skeletal muscle degeneration is more prominent in model mice than in human patients [8]. A novel human disease model that more accurately recapitulates SBMA patients’ pathology has been expected for more precise pathophysiological analysis and the development of novel therapeutics
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