المؤلفون: Helmuth Steinmetz, Donat Kögel, Georg Auburger, Filomena Ricciardi, Michael Bonin, Olaf Riess, Alexander Kurz, Hans-Hermann Hoepken, Suzana Gispert, Michael Klinkenberg, Thomas Gasser, Mekhman Azizov, Blas Morales-Gordo

المصدر: Experimental neurology. 212(2)

مصطلحات موضوعية: Male, Programmed cell death, Time Factors, Glycine, PINK1, Biology, medicine.disease_cause, chemistry.chemical_compound, Developmental Neuroscience, Downregulation and upregulation, Gene expression, medicine, Humans, Fibroblast, Cells, Cultured, Aged, Alpha-synuclein, Family Health, Aspartic Acid, Neurodegeneration, Parkinson Disease, Fibroblasts, Middle Aged, medicine.disease, Mitochondria, medicine.anatomical_structure, Neurology, chemistry, Gene Expression Regulation, Immunology, Mutation, Cancer research, alpha-Synuclein, Female, Protein Kinases, Oxidative stress

الوصف: Parkinson's disease (PD) is a neurodegenerative movement disorder of advanced age with largely unknown etiology, but well documented tissue damage from oxidative stress. Increased α-synuclein ( SNCA ) expression is known to cause a rare form of PD, early-onset autosomal dominant PARK4. We have previously shown that loss-of-function mutations of the mitochondrial kinase PINK1 which cause the early-onset recessive PARK6 variant result in oxidative damage in patient fibroblasts. We now investigated the molecular chain of events from mitochondrial dysfunction to cell death which is largely unknown. Primary skin fibroblast cultures from patients were analysed for gene expression anomalies. In G309D-PINK1 patient fibroblasts, mainly genes regulated by oxidative stress, as well as genes encoding synaptic proteins such as SNCA showed altered expression. The induction of SNCA was also observed in control fibroblasts with knock-down of PINK1. The induction of SNCA expression was found to constitute a specific disease biomarker in sporadic PD patient fibroblasts. To understand the mechanism of this induction, we exposed control fibroblasts to oxidative, proteasomal and endoplasmic reticulum stress and were able to trigger the SNCA expression upregulation. Our data indicate that loss-of-function of PINK1 leads to enhanced alpha-synuclein expression and altered cell–cell contact. Alpha-synuclein induction might represent a common event for different variants of PD as well as a PD-specific trigger of neurodegeneration. We propose that the expression changes described might potentially serve as biomarkers that allow objective PD patient diagnosis in an accessible, peripheral tissue.

الوصول الحر: https://explore.openaire.eu/search/publication?articleId=doi_dedup___::985246b805ac8b7c26f897428c076272Test
https://pubmed.ncbi.nlm.nih.gov/19166835Test

المؤلفون: Suzana Gispert, Blas Morales, Alexei P. Kudin, Ulrich Brandt, Oliver Wingerter, Hans-Hermann Hoepken, Alexander Mülsch, Stefan Dröse, Klaus Müller, Robert L. Nussbaum, Wolfram S. Kunz, Georg Auburger, Domenico Del Turco, Thomas Deller, Brunhilde Wirth

المصدر: Neurobiology of Disease, Vol 25, Iss 2, Pp 401-411 (2007)

مصطلحات موضوعية: MnSOD, Adult, Male, medicine.medical_specialty, Antioxidant, medicine.medical_treatment, Glutathione reductase, Substantia nigra, PINK1, Mitochondrion, Biology, medicine.disease_cause, lcsh:RC321-571, Lipid peroxidation, chemistry.chemical_compound, Superoxides, Malondialdehyde, Internal medicine, medicine, Humans, Lymphocytes, lcsh:Neurosciences. Biological psychiatry. Neuropsychiatry, Cell Line, Transformed, Electron Transport Complex I, Superoxide Dismutase, Parkinson Disease, Glutathione, Fibroblasts, Middle Aged, Mitochondria, Oxidative Stress, Endocrinology, Neurology, chemistry, Biochemistry, Female, Lipid Peroxidation, Protein Kinases, Oxidative stress

الوصف: Oxidative stress and protein aggregation are biochemical hallmarks of Parkinson’s disease (PD), a frequent sporadic late-onset degenerative disorder particularly of dopaminergic neurons in the substantia nigra, resulting in impaired spontaneous movement. PARK6 is a rare autosomal-recessively inherited disorder, mimicking the clinical picture of PD with earlier onset and slower progression. Genetic data demonstrated PARK6 to be caused by mutations in the protein PINK1, which is localized to mitochondria and has a serine–threonine kinase domain. To study the effect of PINK1 mutations on oxidative stress, we used primary fibroblasts and immortalized lymphoblasts from three patients homozygous for G309D-PINK1. Oxidative stress was evident from increases in lipid peroxidation and in antioxidant defenses by mitochondrial superoxide dismutase and glutathione. Elevated levels of glutathione reductase and glutathione- S -transferase were also observed. As a putative cause of oxidation, a mild decrease in complex I activity and a trend to superoxide elevation were detectable. These data indicate that PINK1 function is critical to prevent oxidative damage and that peripheral cells may be useful for studies of progression and therapy of PARK6.

الوصول الحر: https://explore.openaire.eu/search/publication?articleId=doi_dedup___::30655712f53a28d63cc5520ea8afb8c2Test
https://pubmed.ncbi.nlm.nih.gov/17141510Test