Activity of protein phosphatase calcineurin is decreased in sporadic and familial amyotrophic lateral sclerosispatients.
Calcineurin (CaN) is a Ser/Thr protein phosphatase involved in a wide range of cellular responses to calcium mobilizing signals. Previous evidence supports the notion that calcineurin is oxidatively inhibited by mutant Cu, Zn superoxide dismutase (SOD1) typical of familial ALS patients in vitro and in transgenic mice. We report that calcineurin activity is markedly inhibited in lymphocytes from 37 sporadic, eight familial ALS patients and an asymptomatic subject carrying an SOD1 mutation as compared to 28 healthy controls. Two other healthy subjects, heterozygous for the D90A mutation from a recessive pedigree, have normal calcineurin activity. Immunoreactive CaN protein, age, sex and riluzole treatment are not related to calcineurin activity in samples from patients. However, we have observed a marked increase in total protein oxidation in extracts from ALS lymphocytes, as compared to extracts from control subjects. These data confirm that modification of calcineurin activity and possibly of calcineurin-mediated pathways of signal transduction (including modulation of apoptotic neuronal death) may contribute to the pathogenesis of ALS.
Ferri
Alberto
A
Ist. di Neuroscienze CNR, Sez. Psicobiologia e Psicofarmacologia, Rome, Italy.
Nencini
Monica
M
Battistini
Stefania
S
Giannini
Fabio
F
Siciliano
Gabriele
G
Casali
Carlo
C
Damiano
Maria G
MG
Ceroni
Mauro
M
Chiò
Adriano
A
Rotilio
Giuseppe
G
Carrì
Maria Teresa
MT
D000328:Adult; D000368:Aged; D000369:Aged, 80 and over; D000690:Amyotrophic Lateral Sclerosis / Q000188:drug therapy / Q000235:genetics / Q000378:metabolism*; D015153:Blotting, Western / Q000379:methods; D019703:Calcineurin / Q000378:metabolism*; D016022:Case-Control Studies; D005260:Female; D006801:Humans; D008214:Lymphocytes / Q000187:drug effects / Q000378:metabolism*; D008297:Male; D008875:Middle Aged; D018696:Neuroprotective Agents / Q000627:therapeutic use; D028861:Nuclear Pore Complex Proteins / Q000378:metabolism; D019782:Riluzole / Q000627:therapeutic use; D013482:Superoxide Dismutase / Q000235:genetics / Q000378:metabolism; D000072105:Superoxide Dismutase-1
C085914:NUP214 protein, human; D018696:Neuroprotective Agents; D028861:Nuclear Pore Complex Proteins; C000606290:SOD1 protein, human; D019782:Riluzole; C000606291:Sod1 protein, mouse; D013482:Superoxide Dismutase; D000072105:Superoxide Dismutase-1; D019703:Calcineurin