Dc. Shields et al., A putative mechanism of demyelination in multiple sclerosis by a proteolytic enzyme, calpain, P NAS US, 96(20), 1999, pp. 11486-11491
Citations number
48
Categorie Soggetti
Multidisciplinary
Journal title
PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA
In autoimmune demyelinating diseases such as multiple sclerosis (MS), the d
egradation of myelin proteins results in destabilization of the myelin shea
th. Thus, proteases have been implicated in myelin protein degradation, and
recent studies have demonstrated increased expression and activity of a ca
lcium-activated neutral proteinase (calpain) in experimental allergic encep
halomyelitis, the corresponding animal model of MS. In the present study, c
alpain activity and expression (at translational and transcriptional levels
) were evaluated in white matter from human patients with MS and Parkinson'
s and Alzheimer's diseases and compared with that of white matter from norm
al controls. Western blot analysis revealed that levels of the active form
of calpain and calpain-specific degradation products (fodrin) were increase
d by 90.1% and 52.7%, respectively, in MS plaques compared with normal whit
e matter. Calpain translational expression was up-regulated by 462.5% in MS
plaques compared with controls, although levels of the specific endogenous
inhibitor, calpastatin, were not altered significantly. At the transcripti
onal level, no significant changes in calpain or calpastatin expression wer
e detected by reverse transcription-PCR. Using double immunofluorescent lab
eling, increased calpain expression was observed in reactive astrocytes, ac
tivated T cells, and activated mononuclear phagocytes in and adjacent to de
myelinating lesions. Calpain activity and translational expression were not
increased significantly in white matter from patients with Parkinson's or
Alzheimer's diseases compared with that of normal controls. Because calpain
degrades all major myelin proteins, the increased activity and expression
of this proteinase may play a critical role in myelinolysis in autoimmune d
emyelinating diseases such as MS.