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The C9orf72 protein interacts with Rab1a and the ULK1 complex to regulate initiation of autophagy

Authors Christopher P Webster1,‡, Emma F Smith1,‡, Claudia S Bauer1, Annekathrin Moller1, Guillaume M
Hautbergue1, Laura Ferraiuolo1, Monika A Myszczynska1, Adrian Higginbottom1, Matthew J Walsh1, Alexander
J Whitworth2,†, Brian K Kaspar3, KathrinMeyer3, Pamela J Shaw1, Andrew J Grierson1,§ & Kurt J De Vos1,§,*
Affiliations 1Sheffield Institute for Translational Neuroscience (SITraN), Department of Neuroscience University of Sheffield, Sheffield, UK
2Department of Biomedical Science, University of Sheffield, Sheffield, UK
3The Research Institute at Nationwide Children's Hospital, Columbus, OH, USA
4MRC Mitochondrial Biology Unit, Cambridge, UK
↵*Corresponding author. Tel: +44 114 222 2241; E‐mail:
↵† These authors contributed equally to this work

↵‡ These authors contributed equally to this work
Application Area Neuroscience
General Fluorescence Microscopy
Abstract A GGGGCC hexanucleotide repeat expansion in the C9orf72 gene is
the most common genetic cause of amyotrophic lateral sclerosis
and frontotemporal dementia (C9ALS/FTD). C9orf72 encodes two
C9orf72 protein isoforms of unclear function. Reduced levels of
C9orf72 expression have been reported in C9ALS/FTD patients, and
although C9orf72 haploinsufficiency has been proposed to contribute
to C9ALS/FTD, its significance is not yet clear. Here, we report
that C9orf72 interacts with Rab1a and the Unc-51-like kinase 1
(ULK1) autophagy initiation complex. As a Rab1a effector, C9orf72
controls initiation of autophagy by regulating the Rab1a-dependent
trafficking of the ULK1 autophagy initiation complex to the
phagophore. Accordingly, reduction of C9orf72 expression in cell
lines and primary neurons attenuated autophagy and caused accumulation
of p62-positive puncta reminiscent of the p62 pathology
observed in C9ALS/FTD patients. Finally, basal levels of autophagy
were markedly reduced in C9ALS/FTD patient-derived iNeurons. Thus,
our data identify C9orf72 as a novel Rab1a effector in the regulation
of autophagy and indicate that C9orf72 haploinsufficiency and associated
reductions in autophagy might be the underlying cause of
C9ALS/FTD-associated p62 pathology.
Extract Images were recorded using appropriate filtersets (Omega Optical and Chroma Technology) using MicroManager 1.4 software (Edelstein et al, 2014) on a Zeiss Axioplan2 microscope fitted with a Hamamatsu C4880‐80 or Retiga R3 (QImaging) CCD camera, PE‐300 LED illumination (CoolLED)
Product Associated Features CoolLED’s pE-300white offers intense, broad-spectrum LED illumination for imaging most common fluorescent stains.
Diascopic Technique
Live Cell Issues
Product Type pE-300white pE-4000
Year of Publication 2016
Country of Publication UK

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