Pathology and function of nuclear amyloid

Stepwise fibrillation of proteins to amyloid structures and amyloid-like protein aggregates occurs naturally or is disease associated. The hallmark of amyloid aggregation is conversion of otherwise soluble proteins into β-sheet conformations that locate extracellularly, in the cytoplasm or in the cell nucleus. Formation of amyloid-like protein aggregates unifies superficially unrelated human conditions such as Alzheimer, Parkinson, or Huntington disease that are therefore consolidated as neurodegenerative deposition diseases. In brains of patients with Alzheimer disease amyloid β peptides (Aβs) deposit in extracellular plaques or fibrils, whereas tau protein is enriched in intraneuronal neurofibrillary tangles. Protein deposition in Parkinson disease occurs as characteristic Lewy body inclusions in the cytoplasm of residual substantia nigra and dopaminergic striatal neurons. Huntington disease constitutes one out of nine neurodegenerative disorders that are characterized by aberrant deposition of signature proteins containing unstable homopolymeric repeats of the amino acid glutamine (polyQ). Neuronal cells of patients with polyQ-repeat-length diseases are characterized by occurrence of microscopically discernible nuclear inclusions (NIs) that contain proteins with expanded polyQ stretches, components of the ubiquitin-proteasome system (UPS), and other cellular proteins. Aggregates can likewise be observed in other neural compartments such as the cytoplasm, dendrites, and axon terminals. A common feature of such inclusions is the recruitment of mutated, misfolded, and waste proteins that leave solution because of the tendency of normally buried hydrophobic domains to associate with one another. The presence of proteasome-dependent proteolytic activity in NIs indicates that misfolded or excess polypeptides form intracellular aggregates before their degradation. Yet, the role of nuclear protein aggregates in disease pathology is still unknown, and their assumed function ranges from being cytotoxic to benign or even neuroprotective. This review compiles current knowledge about nuclear protein aggregation, e.g., amyloid deposition with special emphasis on their protein composition mandating the idea that this composition reflects perturbed protein interaction networks and holds the key for a better understanding of underlying pathologic as well as physiologic events.