Atypical protein kinase C in neurodegenerative disease II:: PKCι/λ in tauopathies and α-synucleinopathies

To study the role of atypical protein kinase C (aPKC) in neurodegenerative disease, we investigated the distribution of PKCu/X, an aPKC isoform, in a variety of tauopathies and alpha-synucleinopathies. Immmnohistochemical study revealed PKCl/lambda within tau-positive neurofibrillary inclusions in Alzheimer disease (AD), progressive supranuclear palsy, corticobasal degeneration (CBD), and Pick disease (PiD), within alpha-synuclein-positive Lewy bodies in idiopathic Parkinson disease and dementia with Lewy bodies, as well as within glial inclusions in multisystem atrophy. We also observed PKCl/lambda label of actin-rich Hirano bodies in AD, PiD, and elderly individuals. Double immunolabeling and fluorescence resonance energy transfer demonstrated close physical association between PKCl/lambda and phospho-tau or alpha-synuclein in some neurofibrillary tangles and Lewy bodies. Furthermore, PKCl/lambda colocalized with p62, a chaperone protein that binds to both aPKC and ubiquitin, in most of these inclusions. PKCl/lambda also closely associated with the inactivated form of glycogen synthase kinase-3 beta, GSK-3 beta[ser9]. Together, these findings suggest that PKCl/lambda may play a role in common mechanisms involving the pathogenesis of neurodegenerative disease.