Activated p38MAPK is a novel component of the intracellular inclusions found in human amyotrophic lateral sclerosis and mutant SOD1 transgenic mice.
Cytoskeletal abnormalities with accumulation of ubiquilated inclusions in the anterior horn cells are a pathological hallmark of both familial and sporadic amyotrophic lateral sclerosis (ALS) and of mouse models for ALS. Phosphorylated neurofilaments besides ubiquitin and dorfin have been identified as one of the major components of the abnormal intracellular perikaryal aggregates. As we recently found that p38 mitogen-activated protein kinase (p38MAPK) colocalized with phosphorylated neurofilaments in spinal motor neurons of SOD1 mutant mice, a model of familial ALS, we investigated whether this kinase also contributed to the inclusions found in ALS patients and SOD1 mutant mice. Intense immunoreactivity for activated p38MAPK was observed in degenerating motor neurons and reactive astrocytes in ALS cases. The intracellular immunostaining for activated p38MAPK appeared in some neurons as filamentous skein-like and ball-like inclusions, with an immunohistochemical pattern identical to that of ubiquitin. Intracellular p38MAPK-positive aggregates containing ubiquitin and neurofilaments were also found in the spinal motor neurons of SOD1 mutant mice. Our observations indicate that activation of p38MAPK might contribute significantly to the pathology of motor neurons in ALS.
Laboratory of Molecular Neurobiology, Dept. Neuroscience, Istituto di Ricerche Farmacologiche Mario Negri, Via Eritrea, 62, 20157 Milano, Italy. bendotti@marionegri.it
Caterina
C
Bendotti
Cristiana
C
Atzori
Roberto
R
Piva
Massimo
M
Tortarolo
Michael J
MJ
Strong
Silvia
S
DeBiasi
Antonio
A
Migheli
D000367:Age Factors; D000368:Aged; D000409:Alanine / Q000235:genetics; D000690:Amyotrophic Lateral Sclerosis / Q000201:enzymology* / Q000473:pathology; D000818:Animals; D005260:Female; D005998:Glycine / Q000235:genetics; D006801:Humans; D007150:Immunohistochemistry / Q000379:methods; D002479:Inclusion Bodies / Q000201:enzymology* / Q000473:pathology / Q000648:ultrastructure; D042541:Intracellular Space / Q000378:metabolism* / Q000473:pathology / Q000648:ultrastructure; D051379:Mice; D008810:Mice, Inbred C57BL; D008822:Mice, Transgenic; D016253:Microscopy, Immunoelectron / Q000379:methods; D008875:Middle Aged; D020928:Mitogen-Activated Protein Kinases / Q000378:metabolism* / Q000648:ultrastructure; D009046:Motor Neurons / Q000166:cytology / Q000201:enzymology; D013116:Spinal Cord / Q000166:cytology / Q000473:pathology / Q000648:ultrastructure; D013482:Superoxide Dismutase / Q000235:genetics / Q000378:metabolism / Q000648:ultrastructure; D000072105:Superoxide Dismutase-1; D025801:Ubiquitin / Q000378:metabolism; D048051:p38 Mitogen-Activated Protein Kinases
C000606290:SOD1 protein, human; D025801:Ubiquitin; C000606291:Sod1 protein, mouse; D013482:Superoxide Dismutase; D000072105:Superoxide Dismutase-1; D020928:Mitogen-Activated Protein Kinases; D048051:p38 Mitogen-Activated Protein Kinases; D000409:Alanine; D005998:Glycine