TY - JOUR
T1 - Human senataxin modulates structural plasticity of the neuromuscular junction in drosophila through a neuronally conserved TGFβ signalling pathway
AU - Mushtaq, Zeeshan
AU - Choudhury, Saumitra Dey
AU - Gangwar, Sri Krishna
AU - Orso, Genny
AU - Kumar, Vimlesh
PY - 2016/9/1
Y1 - 2016/9/1
N2 - Background: Mutations in the human Senataxin (hSETX) gene have been shown to cause two forms of neurodegenerative disorders - a dominant form called amyotrophic lateral sclerosis type 4 (ALS4) and a recessive form called ataxia with oculomotor apraxia type 2 (AOA2). SETX is a putative DNA/RNA helicase involved in RNA metabolism. Although several dominant mutations linked with ALS4 have been identified in SETX, their contribution towards ALS4 pathophysiology is still elusive. Method: In order to model ALS4 in Drosophila and to elucidate the morphological, physiological and signalling consequences, we overexpressed the wild-type and pathological forms of hSETX in Drosophila. Results and Conclusions: The pan-neuronal expression of wild-type or mutant forms of hSETX induced morphological plasticity at neuromuscular junction (NMJ) synapses. Surprisingly, we found that while the NMJ synapses were increased in number, the neuronal function was normal. Analysis of signalling pathways revealed that hSETX modulates the Highwire (Hiw; a conserved neuronal E3 ubiquitin ligase)-dependent bone morphogenetic protein/TGFβ pathway. Thus, our study could pave the way for a better understanding of ALS4 progression by SETX through the regulation of neuronal E3 ubiquitin pathways.
AB - Background: Mutations in the human Senataxin (hSETX) gene have been shown to cause two forms of neurodegenerative disorders - a dominant form called amyotrophic lateral sclerosis type 4 (ALS4) and a recessive form called ataxia with oculomotor apraxia type 2 (AOA2). SETX is a putative DNA/RNA helicase involved in RNA metabolism. Although several dominant mutations linked with ALS4 have been identified in SETX, their contribution towards ALS4 pathophysiology is still elusive. Method: In order to model ALS4 in Drosophila and to elucidate the morphological, physiological and signalling consequences, we overexpressed the wild-type and pathological forms of hSETX in Drosophila. Results and Conclusions: The pan-neuronal expression of wild-type or mutant forms of hSETX induced morphological plasticity at neuromuscular junction (NMJ) synapses. Surprisingly, we found that while the NMJ synapses were increased in number, the neuronal function was normal. Analysis of signalling pathways revealed that hSETX modulates the Highwire (Hiw; a conserved neuronal E3 ubiquitin ligase)-dependent bone morphogenetic protein/TGFβ pathway. Thus, our study could pave the way for a better understanding of ALS4 progression by SETX through the regulation of neuronal E3 ubiquitin pathways.
KW - Drosophila
KW - Neuromuscular junction
KW - Senataxin overexpression
KW - Structural plasticity
KW - Synapses
KW - TGFβ signalling
UR - http://www.scopus.com/inward/record.url?scp=84987668108&partnerID=8YFLogxK
UR - http://www.scopus.com/inward/citedby.url?scp=84987668108&partnerID=8YFLogxK
U2 - 10.1159/000445435
DO - 10.1159/000445435
M3 - Article
AN - SCOPUS:84987668108
VL - 16
SP - 324
EP - 336
JO - Neurodegenerative Diseases
JF - Neurodegenerative Diseases
SN - 1660-2854
IS - 5-6
ER -