Deregulation of PKN1 activity disrupts neurofilament organisation and axonal transport.
Neurofilaments are synthesised in neuronal cell bodies and then transported through axons. Damage to neurofilament transport is seen in amyotrophic lateral sclerosis (ALS). Here, we show that PKN1, a neurofilament head-rod domain kinase is cleaved and activated in SOD1G93A transgenic mice that are a model of ALS. Moreover, we demonstrate that glutamate, a proposed toxic mechanism in ALS leads to caspase cleavage and disruption of PKN1 in neurons. Finally, we demonstrate that a cleaved form of PKN1 but not wild-type PKN1 disrupts neurofilament organisation and axonal transport. Thus, deregulation of PKN1 may contribute to the pathogenic process in ALS.
Manser
Catherine
C
MRC Centre for Neurodegeneration Research, Department of Neuroscience P037, Institute of Psychiatry, King's College, De Crespigny Park, Denmark Hill, London SE58AF, United Kingdom.
Stevenson
Alison
A
MRC Centre for Neurodegeneration Research, Department of Neuroscience P037, Institute of Psychiatry, King's College, De Crespigny Park, Denmark Hill, London SE58AF, United Kingdom.
Banner
Steven
S
MRC Centre for Neurodegeneration Research, Department of Neuroscience P037, Institute of Psychiatry, King's College, De Crespigny Park, Denmark Hill, London SE58AF, United Kingdom.
Davies
Jennifer
J
MRC Centre for Neurodegeneration Research, Department of Neuroscience P037, Institute of Psychiatry, King's College, De Crespigny Park, Denmark Hill, London SE58AF, United Kingdom.
Tudor
Elizabeth L
EL
MRC Centre for Neurodegeneration Research, Department of Neuroscience P037, Institute of Psychiatry, King's College, De Crespigny Park, Denmark Hill, London SE58AF, United Kingdom.
Ono
Yoshitaka
Y
Biosignal Research Center, Kobe University, Kobe 657-8501, Japan.
Leigh
P Nigel
PN
MRC Centre for Neurodegeneration Research, Department of Neuroscience P037, Institute of Psychiatry, King's College, De Crespigny Park, Denmark Hill, London SE58AF, United Kingdom.
McLoughlin
Declan M
DM
MRC Centre for Neurodegeneration Research, Department of Neuroscience P037, Institute of Psychiatry, King's College, De Crespigny Park, Denmark Hill, London SE58AF, United Kingdom.
Shaw
Christopher E
CE
MRC Centre for Neurodegeneration Research, Department of Neuroscience P037, Institute of Psychiatry, King's College, De Crespigny Park, Denmark Hill, London SE58AF, United Kingdom.
Miller
Christopher C J
CCJ
MRC Centre for Neurodegeneration Research, Department of Neuroscience P037, Institute of Psychiatry, King's College, De Crespigny Park, Denmark Hill, London SE58AF, United Kingdom.
D000690:Amyotrophic Lateral Sclerosis / Q000201:enzymology* / Q000209:etiology / Q000235:genetics; D000818:Animals; D001370:Axonal Transport / Q000235:genetics; D053148:Caspase 3 / Q000378:metabolism; D004195:Disease Models, Animal; D018698:Glutamic Acid / Q000633:toxicity; D006801:Humans; D008297:Male; D051379:Mice; D008822:Mice, Transgenic; D016900:Neurofilament Proteins / Q000378:metabolism* / Q000648:ultrastructure*; D009474:Neurons / Q000187:drug effects / Q000201:enzymology / Q000648:ultrastructure; D011493:Protein Kinase C / Q000235:genetics / Q000378:metabolism*; D051381:Rats; D013116:Spinal Cord / Q000378:metabolism; D013482:Superoxide Dismutase / Q000235:genetics; D000072105:Superoxide Dismutase-1
D016900:Neurofilament Proteins; C000606290:SOD1 protein, human; D018698:Glutamic Acid; C000606291:Sod1 protein, mouse; C000606292:Sod1 protein, rat; D013482:Superoxide Dismutase; D000072105:Superoxide Dismutase-1; C061570:protein kinase N; D011493:Protein Kinase C; D053148:Caspase 3