Abstract
Protein misfolding is a distinguishing feature of a number of neurodegenerative diseases. Accumulation of misfolded protein often results in cellular lesions, the location of lesions correlating with the nature of symptoms. Alzheimer’s disease (AD), Progressive Supranuclear Palsy (PSP), Corticobasal Degeneration (CBD) and Pick’s Disease (PiD) all present with pathological lesions containing hyperphosphorylated filamentous tau protein; however, the location and type of lesion varies. In addition, granulovacuolar degeneration (GVD) bodies have been reported within hippocampal pyramidal neurons in AD, PSP, CBD and PiD tissue. GVDs are defined as electron-dense granules within double membrane-bound cytoplasmic vacuoles. We have previously reported that the phosphorylated form of stress-activated protein kinase/c-Jun N-terminal kinase (p-SAPK/JNK) accumulates in granules within hippocampal pyramidal cell bodies in AD tissue at the time that hyperphosphorylated tau begins to aggregate into early-stage NFTs. We now report that p-SAPK/JNK granules are found within the hippocampal CA1 region of PSP, CBD and PiD cases as well and that these granules are likely GVD bodies. Quantitatively, p-SAPK/JNK granules and GVDs are found in comparable numbers of CA1 cells. Within cells, p-SAPK/JNK granules are distributed throughout the cytoplasm in a manner similar to the distribution of GVDs and a subset of granules co-localize with GVD markers. Ultrastructurally, p-SAPK/JNK granules are located in large cytoplasmic vacuoles, thereby fitting the definition of a GVD body. With the implication of granular p-SAPK/JNK as a marker of GVDs, our study strongly suggests that a heterogeneous group of proteins form GVDs. The mechanism of GVD formation is therefore an interesting one, and is likely separate and distinct from the mechanism of tau inclusion formation.
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Acknowledgments
The authors thank Dr. Angela Guillozet-Bongaarts (Northwestern University) for critical reading of the final versions of the manuscript and Dr. Akihiko Takashima and Dr. Naruhiko Sahara (RIKEN Institute) for help and advice with preliminary studies; Lennell Reynolds, Jr. from the Northwestern University Cell Imaging Facility for tissue embedding and ultrathin sectioning as well as for his expertise and advice with transmission electron microscopy; Dr. Eileen Bigio from the Northwestern University Cognitive Neurology and Alzheimer’s Disease Center and Dr. Dennis Dickson from the Mayo Clinic Alzheimer’s Disease Research Center for providing us with tissue; Dr. Merl F. Hoekstra from the ICOS Corporation for providing our laboratory with the anti-CKIδ and anti-CK1α antibodies; and Dr. Peter Davies from AECOM for allowing us to use the PHF-1 antibody. We are especially grateful to the patients and their families who have made this study possible. This work was supported by NIH grants AG09466 and AG021661.
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Lagalwar, S., Berry, R.W. & Binder, L.I. Relation of hippocampal phospho-SAPK/JNK granules in Alzheimer’s disease and tauopathies to granulovacuolar degeneration bodies. Acta Neuropathol 113, 63–73 (2007). https://doi.org/10.1007/s00401-006-0159-4
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DOI: https://doi.org/10.1007/s00401-006-0159-4