Variants of the heavy neurofilament subunit are associated with the development of amyotrophic lateral sclerosis.
Amyotrophic lateral sclerosis (ALS) is a neurodegenerative disorder primarily affecting motor neurons. The etiology of the majority of cases remains unknown. Recent findings from several laboratories suggest a role for neurofilaments in the development of motor neuron disorders. The C-terminal region of the human neurofilament heavy subunit (NEFH) contains a unique functional domain consisting of 43 repeat motifs of the amino acids Lys-Ser-Pro (KSP). This C-terminal region of NEFH forms the sidearm projections which cross-link the neurofilaments. Previously, we have demonstrated polymorphism in the C-terminal region of the human NEFH: an allelic variant of a slightly larger molecular size, containing an additional KSP phosphorylation motif. Novel mutations in this region were found in five ALS patients. We propose that changes in the KSP-repeat domain may affect the cross-linking properties of the heavy neurofilament subunit and perhaps contribute to the development of neurofilamentous swellings in motor neurons, a hallmark of ALS.
Centre for Research in Neuroscience, McGill University, Montreal, Quebec, Canada.
D A
DA
Figlewicz
A
A
Krizus
M G
MG
Martinoli
V
V
Meininger
M
M
Dib
G A
GA
Rouleau
J P
JP
Julien
D000368:Aged; D000595:Amino Acid Sequence; D000690:Amyotrophic Lateral Sclerosis / Q000235:genetics* / Q000503:physiopathology; D001483:Base Sequence; D003001:Cloning, Molecular; D004247:DNA / Q000097:blood; D017931:DNA Primers; D005260:Female; D014644:Genetic Variation; D006801:Humans; D046911:Macromolecular Substances; D008297:Male; D008875:Middle Aged; D008969:Molecular Sequence Data; D016900:Neurofilament Proteins / Q000235:genetics*; D016133:Polymerase Chain Reaction; D011110:Polymorphism, Genetic; D012091:Repetitive Sequences, Nucleic Acid
D017931:DNA Primers; D046911:Macromolecular Substances; D016900:Neurofilament Proteins; D004247:DNA