title: Molecular misreading: the occurrence of frameshift proteins in different diseases.
abstract: Neuronal homoeostasis requires a constant balance between biosynthetic and catabolic processes. Eukaryotic cells primarily use two distinct mechanisms for degradation: the proteasome and autophagy of aggregates by the lysosomes. We focused on the UPS (ubiquitin-proteasome system). As a result of molecular misreading, misframed UBB (ubiquitin B) (UBB+1) is generated. UBB+1 accumulates in the neuritic plaques and neurofibrillary tangles in all patients with AD (Alzheimer's disease) and in the neuronal and glial hallmarks of other tauopathies and in polyglutamine diseases such as Huntington's disease. UBB+1 is not present in synucleinopathies such as Parkinson's disease. We showed that UBB+1 causes UPS dysfunction, aggregation and apoptotic cell death. UBB+1 is also present in non-neurological cells, hepatocytes of the diseased liver and in muscles during inclusion body myositis. Other frequently occurring (age-related) diseases such as Type 2 (non-insulin-dependent) diabetes mellitus are currently under investigation. These findings point to the importance of the UPS in diseases and open new avenues for target identification of the main players of the UPS. Treatment of these diseases with tools (e.g. viral RNA interference constructs) to intervene with specific targets is the next step.
authors.affiliation: Netherlands Institute for Neuroscience, Meibergdreef 47, 1105 BA Amsterdam, The Netherlands. f.van.leeuwen@nin.knaw.nl
authors.forename: F W
authors.initials: FW
authors.lastname: van Leeuwen
authors.forename: J M
authors.initials: JM
authors.lastname: Kros
authors.forename: W
authors.initials: W
authors.lastname: Kamphorst
authors.forename: C
authors.initials: C
authors.lastname: van Schravendijk
authors.forename: R A I
authors.initials: RA
authors.lastname: de Vos
mesh_terms: D000595:Amino Acid Sequence; D016368:Frameshift Mutation; D030342:Genetic Diseases, Inborn / Q000235:genetics*; D006801:Humans; D008969:Molecular Sequence Data; D046988:Proteasome Endopeptidase Complex / Q000235:genetics / Q000378:metabolism; D011506:Proteins / Q000235:genetics*; D014158:Transcription, Genetic; D025801:Ubiquitin / Q000235:genetics
chemical_list: D011506:Proteins; C479419:UBB protein, human; D025801:Ubiquitin; D046988:Proteasome Endopeptidase Complex