title: Parkin loss-of-function pathology: Premature neuronal senescence induced by high levels of reactive oxygen species?
abstract: Parkinson's and Alzheimer's diseases (PD and AD, respectively) are considered to be diseases of advanced brain ageing, which seems to involve high levels of reactive oxygen species (ROS). AD neurodegeneration is initially apparent in the hippocampus; as AD progresses, many more brain regions are affected. PD-associated neurodegeneration is relatively limited to dopaminergic neurons of the substantia nigra pars compacta (SNpc), especially in cases in which patients inherit particular disease-causing mutations. Thus, the task of elucidating mechanisms by which loss of function of one particular protein triggers death of a subset of neurons may be more approachable. Understanding the mechanisms of neurodegeneration in these forms of PD may not only shed light on avenues leading toward therapeutic strategies in PD and other neurodegenerative diseases, but also on those leading toward understanding natural ageing. Neurodegeneration in PD patients harboring homozygous loss-of-function mutations in the PARK2 gene may result from unbalanced levels of ROS, which are mostly produced in mitochondria and can irreparably damage macromolecules and trigger apoptosis. This review discusses mitochondrial sources of ROS, how ROS can trigger apoptosis, mechanisms by which Parkin loss-of-function may cause neurodegeneration by increasing ROS levels, and concludes with hypotheses regarding selective SNpc dopaminergic neuron vulnerability.
authors.affiliation: Midwestern University, 19555 N 59th Avenue, Glendale, AZ, 85308, USA. Electronic address: lbuhlm@midwestern.edu.
authors.forename: Lori M
authors.initials: LM
authors.lastname: Buhlman
mesh_terms: D000544:Alzheimer Disease / Q000235:genetics / Q000378:metabolism* / Q000473:pathology; D000818:Animals; D017209:Apoptosis; D016922:Cellular Senescence; D059290:Dopaminergic Neurons / Q000378:metabolism* / Q000473:pathology; D006801:Humans; D010300:Parkinson Disease / Q000235:genetics / Q000378:metabolism* / Q000473:pathology; D065842:Pars Compacta / Q000378:metabolism* / Q000473:pathology; D017382:Reactive Oxygen Species / Q000378:metabolism*; D044767:Ubiquitin-Protein Ligases / Q000235:genetics / Q000378:metabolism*
chemical_list: D017382:Reactive Oxygen Species; D044767:Ubiquitin-Protein Ligases; C111567:parkin protein
keywords: Mitochondria; Mitophagy; Parkin; Parkinson's disease; Reactive oxygen species; Ubiquitin proteasome system