Phosphorylation and compactness of neurofilaments in multiple sclerosis: Indicators of axonal pathology

Autor: Axel Petzold, Donna Grant, Djordje Gveric, Geoffrey Keir, M Groves, Klaus Schmierer, Miles D. Chapman, Louise Cuzner, Edward J. Thompson
Rok vydání: 2008
Předmět:
NfH
neurofilament heavy chain
Male
Wallerian degeneration
Pathology
SAPK
stress stress-activated protein kinase
RR
relapsing remitting
Cohort Studies
0302 clinical medicine
Neurofilament Proteins
EDSS
expanded disability status scale
Protein Isoforms
Phosphorylation
Aged
80 and over
0303 health sciences
Neurodegeneration
CTRL
control group
Anatomical pathology
Middle Aged
medicine.anatomical_structure
Cytoarchitecture
Neurology
AL
acute lesion
Female
BSP
brain-specific proteins
Neurofilament phosphoforms
Nf
neurofilament
Adult
medicine.medical_specialty
Neurofilament
SP
secondary progressive
Biology
CNS
central nervous system
SAL
subacute lesion
Article
MS
multiple sclerosis
NfL
neurofilament light chain
Axonal injury
White matter
Multiple sclerosis
03 medical and health sciences
Developmental Neuroscience
ELISA
enzyme linked immunoabsorbant assay
medicine
Humans
NAWM
normal-appearing white matter
WM
white matter
IQR
interquartile range
Aged
030304 developmental biology
EM
electron microscopy
ALP
alkaline phosphatase
CL
chronic lesion
PP
primary progressive
medicine.disease
Axons
nervous system
GM
gray matter
Neuroscience
030217 neurology & neurosurgery
Zdroj: Experimental Neurology
ISSN: 0014-4886
DOI: 10.1016/j.expneurol.2008.06.008
Popis: AimsAxonal pathology extends to the axonal cytoarchitecture leaving its signature on axoskeletal proteins. This study investigated whether neurofilament (NfH) phosphorylation would relate to the dynamics of axonal pathology in multiple sclerosis (MS).MethodsNfH phosphoforms (SMI32, SMI34, SMI35) were quantified by ELISA from microdissected samples of control and MS brain and spinal cord. Individual axons were analysed by electron microscopy, densitometrically and morphologically in adjacent tissue sections. Experiments were carried out pre- and post enzymatic dephosphorylation.ResultsIn control tissue a rostro-caudal gradient of NfH indicated an increase in axonal density from the brain gray matter towards the spinal cord. The highest levels of phosphorylated and hyperphosphorylated NfH were found in acute lesions of brain and spinal cord, in contrast to chronic lesions where levels were lower than in white matter, consistent with axonal loss. Dephosphorylated NfH was higher, but less densly packed in MS white matter axons compared to control tissue.ConclusionsThe findings suggest that a less organised/compact axoskeleton or impaired axonal transport may represent an early sign of axonal pathology within the normal appearing white matter in MS. Subsequently a proportional increase of dephosphorylated NfH, aberrant phosphorylation and/or aggregation may occur whilst the protein is transported through the white matter towards the MS plaque, where hyperphosphorylated NfH dominates.
Databáze: OpenAIRE
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