Variants of the heavy neurofilament subunit are associated with the development of amyotrophic lateral sclerosis

Amyotrophic lateral sclerosis (ALS) is a neurodegenerative disorderprimarily affecting motor neurons. The etiology of the majorityof cases remains unknown. Recent findings from several laboratoriessuggest a role for neurofilaments in the development of motorneuron disorders. The C-terminal region of the human neurofilamentheavy subunit (NEFH) contains a unique functional domain consistingof 43 repeat motifs of the amino acids Lys-Ser-Pro (KSP). ThisC-terminal region of NEFH forms the sidearm projections whichcross-link the neurofilaments. Previously, we have demonstratedpolymorphism in the C-terminal region of the human NEFH: anallelic variant of a slightly larger molecular size, containingan additional KSP phosphorylation motif. Novel mutations inthis region were found in five ALS patients. We propose thatchanges in the KSP-repeat domain may affect the cross-linkingproperties of the heavy neurofilament subunit and perhaps contributeto the development of neurofilamentous swellings in motor neurons,a hallmark of ALS.