Nanoparticle-induced cell culture models for degenerative protein aggregation diseases.
Protein aggregates and nuclear inclusions containing components of the ubiquitin-proteasome system, expanded polyglutamine (polyQ) proteins, and transcriptional co-activators characterize cellular responses to stress and are hallmarks of neurodegenerative diseases. For instance, in Huntington's disease, an expansion of a polyQ region causes its aggregation into beta-sheet-containing amyloid fibrils. The biological function of polyQ-containing inclusions is unknown. By means of a silica nanoparticle (NP)-based strategy we induced intranuclear protein inclusions that form amyloid-like structures, recapitulating the protein composition and solubility of polyQ-induced nuclear protein aggregates exactly. We showed that global proteasomal proteolysis increases in silica-NP-treated nuclei and, on the local level, a subpopulation of nuclear inclusions overlaps with focal domains of proteasome-dependent protein degradation. The results suggest that inclusions in the nucleus constitute active proteolysis modules that may serve to concentrate and decompose damaged, mal-folded, or misplaced proteins. While nanoparticle-nucleus interactions turn out to be invaluable tools to study the molecular mechanisms of degenerative protein aggregation diseases, one also has to consider the other side of the coin, namely, emerging environmental risks posed by these very interactions.
Chen
Min
M
Institut für umweltmedizinische Forschung (IUF) at Heinrich-Heine-University Düsseldorf, Düsseldorf, Germany.
von Mikecz
Anna
A
D002460:Cell Line; D006801:Humans; D045586:Intranuclear Inclusion Bodies / Q000187:drug effects* / Q000378:metabolism; D053758:Nanoparticles / Q000737:chemistry / Q000633:toxicity*; D019636:Neurodegenerative Diseases / Q000378:metabolism*; D009687:Nuclear Proteins / Q000737:chemistry / Q000378:metabolism*; D010455:Peptides / Q000378:metabolism; D046988:Proteasome Endopeptidase Complex / Q000187:drug effects / Q000378:metabolism; D011487:Protein Conformation; D017510:Protein Folding; D018570:Risk Assessment; D012822:Silicon Dioxide / Q000737:chemistry / Q000633:toxicity*; D013997:Time Factors; D018675:Toxicity Tests; D054875:Ubiquitination
D009687:Nuclear Proteins; D010455:Peptides; C097188:polyglutamine; D012822:Silicon Dioxide; D046988:Proteasome Endopeptidase Complex