Role of the p62 Protein in the Formation of Neuropathological Cytoplasmic Inclusions

The pathology of aging-associated neurodegenerative disorders typically involves the occurrence of proteinaceous cytoplasmic inclusions in the brain. These inclusions are seen in both neurons and glial cells, affecting disease-specific cell populations. Most types of inclusions associated with cognitive or movement dysfunction are composed of cytoplasmic aggregates of tau or α-synuclein (αS) proteins in aberrant fibrillar forms, thus defining the disease groups of “tauopathies” and “synucleinopathies”. Inclusions are usually accompanied by cell loss, suggesting that their origin is closely linked to the neuronal death and dysfunction that are responsible for the clinical symptoms. The molecular events underlying the formation of cytoplasmic inclusions are poorly understood, but it is increasingly believed that the biogenesis of different types of inclusions may share some common mechanisms. In order to elucidate the mechanisms of inclusion formation and the elicited cellular reactions, it is necessary to identify key proteins involved and investigate their roles in these events. In particular, proteins that may contribute to or regulate the aggregation process are of interest. In the present series of studies, a gene array approach and cellular models were first utilized to identify proteins potentially involved in neurodegenerative phenomena (study I). Following the identification of p62, a signaling protein with several features of interest, the expression of this protein was examined in neuropathology-mimicking conditions in neuronal culture. Subsequently, the involvement of p62 was investigated in disease-associated protein aggregation in the human brain using immunohistochemistry (studies II−IV). In study II, brain specimens from different tauopathies (Alzheimer and Pick diseases) and synucleinopathies (Parkinson disease, dementia with Lewy bodies, and multiple system atrophy) were examined. In study III, the incorporation of p62 was studied in more detail with respect to the tau pathology of Alzheimer disease. In study IV, the morphogenesis of αS-containing inclusions characteristic of Parkinson disease was elucidated. The main findings were: I: The expression of p62 transcript and p62 protein were both prominently upregulated in response to pro-apoptotic conditions and proteasomal inhibition. This upregulation might indicate the activation of survival signaling. II: In both tauopathies and synucleinopathies, the p62 protein was copiously present in the hallmark cytoplasmic inclusions in perikarya but was mostly absent from intraneuritic deposits. III: In the tau pathology of Alzheimer disease, p62 was selectively incorporated into neurofibrillary tangles and represented a relatively early constituent in these structures. IV: The spectrum of perikaryal αS pathology in the substantia nigra pointed to a morphogenetic sequence in which punctate αS deposits, pale bodies, and Lewy bodies arise as successive stages of a complex aggregation process. The engagement of p62 coincided with the formation of compact inclusions, possibly as a part of a cytoprotective response. These findings are compatible with several alternative interpretations, but the pattern of p62 involvement in the various types of inclusions is viewed as evidence that p62 plays a contributory role in their formation. Since inclusions may serve as sinks for potentially noxious proteins, p62 may act to promote cell viability. National Library of Medicine Classification: WL 359 Medical Subject Headings: Alzheimer disease; apoptosis; brain/pathology; human; immunohistochemistry; inclusion bodies; Lewy bodies; neurodegenerative diseases/pathology; neurofibrillary tangles; Parkinson disease; proteins/abnormalities; tauopathies; ubiquitin