the role of molecular chaperones in α-synuclein-related diseases

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14-3-3 proteins, a novel type of molecular chaperons, recognizes the phosphoserine-containing motifs of several target proteins, and regulates various types of signal transduction pathways. We have already reported that 14-3-3 immunoreactivity was localized to the α-synuclein-containing inclusins in brains with Parkinso's disease and multiple system atrophy. We then examined the brains and spinal cords of human α-synuclein (A53T) transgenic mice, and found the immunohistochemical colocalization of α-synuclein and 14-3-3 proteins. We also observed the increased immunoreactivities for some heat shock proteins in brains with synucleinopathies. Furthermore, we performed immunohistochemical studies on 14-3-3 proteins using autopsied spinal cord from patients with amyotrophic lateral sclerosis (ALS), and found 14-3-3 immunoreactivity in the Lewy body-like hyaline inclusions from both sporadic and familial ALS cases. We also observed that 14-3-3 immunoreactivity was localized to the α-synuclein-containing inclusinsin in the anterior horn cells from human SOD1(G93T) trausgenic mice. Moreover, we found the enhanced astroglial immunoexpression of 14-3-3 in the demyelinated lesions from patients with multiple sclerosis and progressive multifocal leukoencephalopathy, and in the cortical and subcortical lesions from patients with Creutzfeldt-Jakob disease, and in the ischemic white matter lesions from Binswanger's disease cases. These data suggest that 14-3-3 proteins may play an important role in the formation of several types of inclusions in brains with neurodegenerative diseases, and that 14-3-3 proteins may be induced in astrocytes under various kinds of pathological conditions, including demyelination, inflammation, and ischemia, and may be associated with the formation of astrogliosis.