Absence of disturbed axonal transport in spinal and bulbar muscular atrophy

Abstract

Spinal and bulbar muscular atrophy (SBMA), or Kennedy's disease, is a late-onset motor neuron disease (MND) caused by an abnormal expansion of the CAG repeat in the androgen receptor (AR) gene on the X-chromosome, encoding a polyglutamine (poly-Q) sequence in the protein product. Mutant poly-Q-expanded AR protein is widely expressed but leads to selective lower motoneuron death. Although the mechanisms that underlie SBMA remain unclear, defective axonal transport has been implicated in MND and other forms of poly-Q disease. Transcriptional dysregulation may also be involved in poly-Q repeat pathology. We therefore examined axonal transport in a mouse model of SBMA recapitulating many aspects of the human disease. We found no difference in the expression levels of motor and the microtubule-associated protein tau, in the spinal cord and sciatic nerve of wild-type (WT) and SBMA mice at various stages of disease progression. Furthermore, we found no alteration in binding properties of motor proteins and tau to microtubules. Moreover, analysis of axonal transport rates both in cultured primary motoneurons in vitro and in vivo in the sciatic nerve of adult WT and mutant SBMA mice demonstrated no overt axonal transport deficits in these systems. Our results therefore indicate that unlike other motoneuron and poly-Q diseases, axonal transport deficits do not play a significant role in the pathogenesis of SBMA.

Regulation of Axonal Transport by Protein Kinases

“…Perfusion of the polyQ-AR in squid axoplasm inhibits the fast axonal transport of membrane-bound organelles through stimulation of JNK3-mediated phosphorylation of the kinesin heavy chain [55]. However, the role of axonal transport deficits in SBMA is controversial, since alterations in axonal transport were not found in vivo in a mouse model of SBMA expressing endogenous levels of polyQ-AR [101].…”

Neurogenic and Myogenic Contributions to Hereditary Motor Neuron Disease

“…Activated c-Jun N-terminal kinase is thought to phosphorylate kinesin-1 heavy chain and inhibit kinesin-1 microtubule-binding activity [37] . However, contradicting findings have now been reported in one SBMA mouse model [38] . In cultured primary motor neurons and in the sciatic nerve, there was no change in the expression levels of components of the axonal transport machinery nor in the microtubule-binding properties of motor proteins, and no overt defects in axonal transport [38] .…”

“…However, contradicting findings have now been reported in one SBMA mouse model [38] . In cultured primary motor neurons and in the sciatic nerve, there was no change in the expression levels of components of the axonal transport machinery nor in the microtubule-binding properties of motor proteins, and no overt defects in axonal transport [38] . Further studies examining the difference in model systems and methodology could help explain the contradictory results and improve our understanding of the potential role of axonal transport defects in SMBA.…”

Pathogenesis and molecular targeted therapy of spinal and bulbar muscular atrophy (SBMA)

“…In a mouse model of SBMA, the nuclear accumulation of the abnormal AR protein induces transcriptional dysregulation of dynactin 1, an axonal motor protein that regulates axonal trafficking (Katsuno et al 2006b). The disruption of retrograde axonal transport was also documented in a knock-in mouse model of SBMA and in mice over-expressing wild-type AR in muscle (Kemp et al 2011), although this was not the case in another mouse model of SBMA (Malik et al 2011).…”