Gene expression analysis reveals early dysregulation of disease pathways in SBMA

Dr. Al La Spada at Duke University, who many of us know through the KDA, has published in Nature, Scientific Reports some research findings that could prove beneficial in future Kennedy's Disease research. 

Note:  You can read the entire report by clicking on the title (link) above.

Gene expression analysis reveals early dysregulation of disease pathways and links Chmp7 to pathogenesis of spinal and bulbar muscular atrophy

Published: 05 March 2019

Bilal Malik, Helen Devine, Rickie Patani, Albert R. La Spada, Michael G. Hanna & Linda Greensmith

Abstract

Spinal and bulbar muscular atrophy (SBMA) results from a CAG repeat expansion within the androgen receptor gene (AR). It is unclear why motor neurons selectively degenerate and there are currently no treatments for this debilitating disease. To uncover the causative genes and pathways involved in motor neuron dysfunction, we undertook transcriptomic profiling of primary embryonic motor neurons from SBMA mice. We show that transcriptional dysregulation occurs early during development in SBMA motor neurons. One gene found to be dysregulated, Chmp7, was also altered in vivo in spinal cord before symptom onset in SBMA mice, and crucially in motor neuron precursor cells derived from SBMA patient stem cells, suggesting that Chmp7 may play a causal role in disease pathogenesis by disrupting the endosome-lysosome system. Furthermore, genes were enriched in SBMA motor neurons in several key pathways including p53, DNA repair, WNT and mitochondrial function. SBMA embryonic motor neurons also displayed dysfunctional mitochondria along with DNA damage, possibly resulting from DNA repair gene dysregulation and/or mitochondrial dysfunction. This indicates that a coordinated dysregulation of multiple pathways leads to development of SBMA. Importantly, our findings suggest that the identified pathways and genes, in particular Chmp7, may serve as potential therapeutic targets in SBMA.

Results

Transcriptomic profiling of SBMA embryonic motor neurons

To characterise early transcriptional dysregulation and establish disease mechanisms in SBMA, we first performed a global transcriptomic screen of purified cultured spinal cord motor neurons from embryonic AR100 and wild-type (WT) mice treated with dihydrotestosterone (DHT), to reflect the ligand dependency of the disease. We found that 178 genes were upregulated, whilst 287 genes were significantly downregulated in AR100 motor neurons compared with WT cultures (Supplementary Information....

...Despite the ubiquitous expression of the causative AR gene and mutant protein, there is as yet no clear explanation for the selective loss of lower motor neurons in the anterior horn of the spinal cord and specific brainstem motor nuclei in SBMA, although high expression of AR within these cell types may be a possible contributory factor....

...Importantly, as no effective treatment or disease modifying therapies are available, the discovery of targets linked with early motor neuron dysfunction may provide promising therapeutic avenues in alleviating the development and course of the disease....

...There were also signs of DNA damage in spinal cord motor neurons of AR100 mice, which may result from downregulation of DNA repair genes and/or mitochondrial dysfunction. The identified pathways and genes, particularly Chmp7, may therefore represent attractive molecular targets for development of a therapeutic approach for SBMA....

Discussion

...Although our results suggest that several pathways may be associated with SBMA pathogenesis, it is possible that mitochondrial and p53 dysfunction are the key, early drivers of disease (Fig. 5A,B). Mitochondrial deficits and p53 dysfunction may act independently and in parallel, but also synergistically to initiate the early features of disease....

...Finally, mitochondrial and p53 deficits may be early instigators of dysfunction possibly acting independently or also synergistically to initiate the early features of disease in motor neurons. Taken together, these findings indicate that an interplay of multiple pathways contribute to the disease pathogenesis 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....