Mouse Study Explores Underlying Cause of Motor Neuron Degeneration in SBMA

A global dysregulation affecting multiple signaling cascades operating inside motor neurons may be the underlying cause of spinal and bulbar muscular atrophy (SBMA), results of a mouse study reveal.

The findings of the study, “Gene expression analysis reveals early dysregulation of disease pathways and links Chmp7 to pathogenesis of spinal and bulbar muscular atrophy,” were published in Scientific Reports.

SBMA, also known as Kennedy’s disease, is a type of spinal muscular atrophy (SMA) that starts in adulthood and is characterized by widespread muscle weakness and wasting in the arms, legs, head, and neck (bulbar involvement).

The disorder is caused by mutations in the androgen receptor (AR) gene — located on the X chromosome — that lead to an abnormal expansion of a CAG nucleotide (the building blocks of DNA) repeat in the AR gene sequence and to the production of a much larger dysfunctional protein.

At this point it is still unclear why motor neurons — the nerve cells responsible for controlling voluntary muscles — start degenerating in SBMA patients, and currently there are no treatment options available.

In this study, a group of researchers from the University College of London (UCL) Queen Square Institute of Neurology set out to uncover the genes and signaling cascades that could be involved in the onset of motor neuron degeneration in SBMA.

To do so, the team first performed a complete analysis of the transcriptomic (the group of all RNA molecules, or transcripts, produced from active genes in a cell or tissue) profile of embryonic spinal cord motor neurons from male mice with SBMA and healthy (wild-type) animals.

All genetic information contained within genes (DNA) is ultimately translated into proteins. However, DNA is first transformed into RNA (transcription), which is ultimately translated into a protein.

Results showed that 178 genes were upregulated (overly active), while 287 were downregulated (under-activated) in motor neurons from SBMA mice compared to healthy animals, indicating that transcriptional dysregulation in SBMA starts at an early stage of development.

One of the genes that was donwregulated in motor neurons from animals with SBMA was Chmp7 (Charged Multivesicular Body Protein 7). Interestingly, the expression levels of this gene also were affected in motor neurons from the spinal cord and lower legs of adult SBMA mice before the onset of symptoms. (Of note, gene expression is the process by which information in a gene is synthesized to create a working product, like a protein.)

Similar alterations in the expression levels of CHMP7 (the equivalent gene of Chmp7 in humans) also were found in motor neurons’ precursors derived from SBMA patients’ induced pluripotent stem cells (iPSCs), suggesting that Chmp7 may play an important role in SBMA development. iPSCs are fully matured cells that are reprogrammed back to a stem cell state, where they are able to grow into any type of cell.

Moreover, the research team discovered that other genes involved in multiple signaling cascades essential for cellular function, such as the tumor suppressor (p53), DNA repair and energy metabolism, also were dysregulated in motor neurons from SBMA animals.

In addition, scientists observed that SBMA motor neurons showed signs of mitochondria (the cell compartments responsible for the production of energy) dysfunction and DNA damage, possibly caused by transcriptional dysregulation of genes involved in energy metabolism and/or DNA repair.

“Taken together, these findings indicate that an interplay of multiple pathways contribute to the disease pathogenesis [development] of SBMA. Significantly, the dysregulated genes and pathways, and in particular Chmp7/CHMP7 identified by our transcriptomic profiling may serve as candidate druggable molecular targets for therapy development in SBMA,” the researchers concluded.