A phenotypically robust model of spinal and bulbar muscular atrophy in Drosophila

Author:

Richardson Kristin1ORCID,Sengupta Medha2,Sujkowski Alyson3ORCID,Libohova Kozeta3,Harris Autumn C.34,Wessells Robert1,Merry Diane E.2,Todi Sokol V.345ORCID

Affiliation:

1. Department of Physiology Wayne State University School of Medicine Detroit Michigan USA

2. Department of Biochemistry and Molecular Biology Thomas Jefferson University Sidney Kimmel Medical College Philadelphia Pennsylvania USA

3. Department of Pharmacology Wayne State University School of Medicine Detroit Michigan USA

4. Maximizing Access to Science Careers Program Wayne State University Detroit Michigan USA

5. Department of Neurology Wayne State University School of Medicine Detroit Michigan USA

Abstract

AbstractSpinal and bulbar muscular atrophy (SBMA) is an X‐linked disorder that affects males who inherit the androgen receptor (AR) gene with an abnormal CAG triplet repeat expansion. The resulting protein contains an elongated polyglutamine (polyQ) tract and causes motor neuron degeneration in an androgen‐dependent manner. The precise molecular sequelae of SBMA are unclear. To assist with its investigation and the identification of therapeutic options, we report here a new model of SBMA in Drosophila melanogaster. We generated transgenic flies that express the full‐length, human AR with a wild‐type or pathogenic polyQ repeat. Each transgene is inserted into the same safe harbor site on the third chromosome of the fly as a single copy and in the same orientation. Expression of pathogenic AR, but not of its wild‐type variant, in neurons or muscles leads to consistent, progressive defects in longevity and motility that are concomitant with polyQ‐expanded AR protein aggregation and reduced complexity in neuromuscular junctions. Additional assays show adult fly eye abnormalities associated with the pathogenic AR species. The detrimental effects of pathogenic AR are accentuated by feeding flies the androgen, dihydrotestosterone. This new, robust SBMA model can be a valuable tool toward future investigations of this incurable disease.

Funder

National Institute of General Medical Sciences

National Institute of Neurological Disorders and Stroke

National Institute on Aging

Publisher

Wiley

Subject

Cellular and Molecular Neuroscience

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