Faculty Collaboration Database

Assessment of cerebral spinal fluid biomarkers and microRNA-mediated disease mechanisms in spinal muscular atrophy patient samples. Hum Mol Genet 2022 Jun 04;31(11):1830-1843

Date

12/18/2021

Pubmed ID

34919695

DOI

10.1093/hmg/ddab365

Scopus ID

2-s2.0-85123796645 (requires institutional sign-in at Scopus site)   19 Citations

Abstract

Cerebral spinal fluid (CSF) is a promising biospecimen for the detection of central nervous system biomarkers to monitor therapeutic efficacy at the cellular level in neurological diseases. Spinal muscular atrophy (SMA) patients receiving intrathecal antisense oligonucleotide (nusinersen) therapy tend to show improved motor function, but the treatment effect on cellular health remains unknown. The objective of this study was to assess the potential of extracellular RNAs and microRNAs in SMA patient CSF as indicators of neuron and glial health following nusinersen treatment. Extracellular RNA analysis of CSF samples revealed ongoing cellular stress related to inflammation and glial differentiation, even after treatment administration. Downregulated microRNA expression associated with SMA-specific or general motor neuron dysfunction in animal and cellular models, tended to increase in nusinersen-treated patient CSF samples and correlated with SMA Type 1 and 2 motor functioning improvements. However, miR-146a, known to be upregulated in SMA-induced pluripotent stem cell (iPSC)-derived astrocytes, showed increased expression in nusinersen-treated CSF samples. We then used mRNA sequencing and multi-electrode arrays to assess the transcriptional and functional effects of miR-146a on healthy and SMA iPSC-derived motor neurons. miR-146a treatment on iPSC-derived motor neurons led to a downregulation of extracellular matrix genes associated with synaptic perineuronal net and alterations in spontaneous electrophysiological activity. Altogether, this study suggests that extracellular RNAs and microRNAs may serve as useful biomarkers to monitor cellular health during nusinersen treatment. Moreover, these data highlight the importance of addressing astrocyte health and response to nusinersen in SMA pathogenesis and treatment strategies.

Author List

Welby E, Rehborg RJ, Harmelink M, Ebert AD

Authors

Allison D. Ebert PhD Center Director, Professor in the Cell Biology Neurobiology and Anatomy department at Medical College of Wisconsin
Emily Welby Research Scientist II in the Cell Biology Neurobiology and Anatomy department at Medical College of Wisconsin

MESH terms used to index this publication - Major topics in bold

Animals
Biomarkers
Humans
MicroRNAs
Motor Neurons
Muscular Atrophy, Spinal
Spinal Muscular Atrophies of Childhood