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.
MRC Centre for Neurodegeneration Research, Department of Neuroscience P037, Institute of Psychiatry, King's College, De Crespigny Park, Denmark Hill, London SE58AF, United Kingdom.
Catherine
C
Manser
MRC Centre for Neurodegeneration Research, Department of Neuroscience P037, Institute of Psychiatry, King's College, De Crespigny Park, Denmark Hill, London SE58AF, United Kingdom.
Alison
A
Stevenson
MRC Centre for Neurodegeneration Research, Department of Neuroscience P037, Institute of Psychiatry, King's College, De Crespigny Park, Denmark Hill, London SE58AF, United Kingdom.
Steven
S
Banner
MRC Centre for Neurodegeneration Research, Department of Neuroscience P037, Institute of Psychiatry, King's College, De Crespigny Park, Denmark Hill, London SE58AF, United Kingdom.
Jennifer
J
Davies
MRC Centre for Neurodegeneration Research, Department of Neuroscience P037, Institute of Psychiatry, King's College, De Crespigny Park, Denmark Hill, London SE58AF, United Kingdom.
Elizabeth L
EL
Tudor
Biosignal Research Center, Kobe University, Kobe 657-8501, Japan.
Yoshitaka
Y
Ono
MRC Centre for Neurodegeneration Research, Department of Neuroscience P037, Institute of Psychiatry, King's College, De Crespigny Park, Denmark Hill, London SE58AF, United Kingdom.
P Nigel
PN
Leigh
MRC Centre for Neurodegeneration Research, Department of Neuroscience P037, Institute of Psychiatry, King's College, De Crespigny Park, Denmark Hill, London SE58AF, United Kingdom.
Declan M
DM
McLoughlin
MRC Centre for Neurodegeneration Research, Department of Neuroscience P037, Institute of Psychiatry, King's College, De Crespigny Park, Denmark Hill, London SE58AF, United Kingdom.
Christopher E
CE
Shaw
MRC Centre for Neurodegeneration Research, Department of Neuroscience P037, Institute of Psychiatry, King's College, De Crespigny Park, Denmark Hill, London SE58AF, United Kingdom.
Christopher C J
CCJ
Miller
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