Increased phosphorylation of collapsin response mediator protein-2 at Thr514 correlates with β-amyloid burden and synaptic deficits in Lewy body dementias.
Collapsin response mediator protein-2 (CRMP2) regulates axonal growth cone extension, and increased CRMP2 phosphorylation may lead to axonal degeneration. Axonal and synaptic pathology is an important feature of Lewy body dementias (LBD), but the state of CRMP2 phosphorylation (pCRMP2) as well as its correlations with markers of neurodegeneration have not been studied in these dementias. Hence, we measured CRMP2 phosphorylation at Thr509, Thr514 and Ser522, as well as markers of β-amyloid (Aβ), tau-phosphorylation, α-synuclein and synaptic function in the postmortem neocortex of a longitudinally assessed cohort of LBD patients characterized by low (Parkinson's disease dementia, PDD) and high (dementia with Lewy bodies, DLB) burden of Alzheimer type pathology. We found specific increases of pCRMP2 at Thr514 in DLB, but not PDD. The increased CRMP2 phosphorylation correlated with fibrillogenic Aβ as well as with losses of markers for axon regeneration (β-III-tubulin) and synaptic integrity (synaptophysin) in LBD. In contrast, pCRMP2 alterations did not correlate with tau-phosphorylation or α-synuclein, and also appear unrelated to immunoreactivities of putative upstream kinases glycogen synthase kinase 3β and cyclin-dependent kinase 5, as well as to protein phosphatase 2A. In conclusion, increased pCRMP2 may underlie the axonal pathology of DLB, and may be a novel therapeutic target. However, antecedent signaling events as well as the nature of pCRMP2 association with Aβ and other neuropathologic markers require further study.
Department of Pharmacology, Yong Loo Lin School of Medicine, National University of Singapore, Unit 09-01, Centre for Translational Medicine (MD6), 14 Medical Drive, Kent Ridge, 117599, Singapore.
Huayang
H
Xing
Department of Pharmacology, Yong Loo Lin School of Medicine, National University of Singapore, Unit 09-01, Centre for Translational Medicine (MD6), 14 Medical Drive, Kent Ridge, 117599, Singapore.|Memory, Ageing and Cognition Centre, National University Health System, Kent Ridge, Singapore.
Yun-An
YA
Lim
Department of Pharmacology, Yong Loo Lin School of Medicine, National University of Singapore, Unit 09-01, Centre for Translational Medicine (MD6), 14 Medical Drive, Kent Ridge, 117599, Singapore.
Joyce R
JR
Chong
Department of Pharmacology, Yong Loo Lin School of Medicine, National University of Singapore, Unit 09-01, Centre for Translational Medicine (MD6), 14 Medical Drive, Kent Ridge, 117599, Singapore.
Jasinda H
JH
Lee
Department of Neurobiology, Care Sciences and Society, Alzheimer's Disease Research Centre, Karolinska Institutet, Novum, Stockholm, Sweden.|Center for Age-Related Diseases, Stavanger University Hospital, Stavanger, Norway.
Dag
D
Aarsland
King's College London, Wolfson Centre for Age-Related Diseases, London, UK.
Clive G
CG
Ballard
King's College London, Wolfson Centre for Age-Related Diseases, London, UK.
Paul T
PT
Francis
Department of Pharmacology, Yong Loo Lin School of Medicine, National University of Singapore, Unit 09-01, Centre for Translational Medicine (MD6), 14 Medical Drive, Kent Ridge, 117599, Singapore.|Memory, Ageing and Cognition Centre, National University Health System, Kent Ridge, Singapore.
Christopher P
CP
Chen
Department of Pharmacology, Yong Loo Lin School of Medicine, National University of Singapore, Unit 09-01, Centre for Translational Medicine (MD6), 14 Medical Drive, Kent Ridge, 117599, Singapore. mitchell.lai@dementia-research.org.|Memory, Ageing and Cognition Centre, National University Health System, Kent Ridge, Singapore. mitchell.lai@dementia-research.org.|King's College London, Wolfson Centre for Age-Related Diseases, London, UK. mitchell.lai@dementia-research.org.
Mitchell K P
0000-0001-7685-1424
MK
Lai
D000369:Aged, 80 and over; D016229:Amyloid beta-Peptides / Q000378:metabolism*; D016022:Case-Control Studies; D015331:Cohort Studies; D051360:Cyclin-Dependent Kinase 5 / Q000378:metabolism; D003600:Cytosol / Q000378:metabolism; D003710:Demography; D005260:Female; D000071679:Glycogen Synthase Kinase 3 beta / Q000378:metabolism; D006801:Humans; D036341:Intercellular Signaling Peptides and Proteins / Q000378:metabolism*; D020961:Lewy Body Disease / Q000378:metabolism* / Q000473:pathology*; D008297:Male; D019579:Neocortex / Q000378:metabolism / Q000473:pathology; D009419:Nerve Tissue Proteins / Q000378:metabolism*; D010766:Phosphorylation; D010769:Phosphothreonine / Q000378:metabolism*; D011180:Postmortem Changes; D013569:Synapses / Q000378:metabolism* / Q000473:pathology*; D016708:Synaptophysin / Q000378:metabolism; D014404:Tubulin / Q000378:metabolism
D016229:Amyloid beta-Peptides; D036341:Intercellular Signaling Peptides and Proteins; D009419:Nerve Tissue Proteins; D016708:Synaptophysin; C498585:TUBB3 protein, human; D014404:Tubulin; C095114:collapsin response mediator protein-2; D010769:Phosphothreonine; D051360:Cyclin-Dependent Kinase 5; D000071679:Glycogen Synthase Kinase 3 beta; C495905:CDK5 protein, human
Axonal pathology; Collapsin response mediator protein-2; Dementia with Lewy bodies; Parkinson’s disease dementia