title: Substantial telomere shortening in the substantia nigra of telomerase-deficient mice does not increase susceptibility to MPTP-induced dopamine depletion.
abstract: The most important risk factor for developing Parkinson's disease (PD) is age. Aging is ascribed to different mechanisms, including telomere shortening. Telomeres consist of repetitive DNA sequences and stabilize chromosome integrity. Currently, however, the data reported on telomere shortening in PD patients are inconsistent. We investigated the effect of telomere shortening in the MPTP mouse model of PD using late-generation telomerase-deficient mice (G3 Terc mice). G3 Terc mice showed a reduction in telomere length in nigral tyrosine hydroxylase-positive neurons by 40%, as indicated by quantitative fluorescence in-situ hybridization. There was no difference in the total motor activity and striatal tissue concentrations of dopamine, DOPAC (3,4-dihydroxyphenylacetic acid), HVA (4-hydroxy-3-methoxyphenylacetic acid), and 3-MT (3-methoxytyramine) concentrations or dopamine turnover in G3 Terc mice in comparison with controls without MPTP treatment. Low-dose MPTP treatment (four injections, 2 h intervals, 2 × 5 and 2 × 7.5 mg/kg) led to a significant decrease in striatal dopamine concentrations that did not differ in G3 Terc mice compared with control mice (19.15 ± 0.44 to 12.81 ± 1.26 ng/mg in control mice in comparison with 19.51 ± 0.59 to 13.56 ± 1.10 ng/mg in G3 Terc mice). In conclusion, telomere shortening does not increase susceptibility to MPTP-induced dopamine depletion in mice. These data indicate that other age-related mechanisms in the brain may play a more important role in enhancing MPTP-induced dopamine depletion.
authors: aCNS Diseases Research, Boehringer Ingelheim Pharma GmbH & Co. KG, Biberach an der Riss bInstitute of Molecular Medicine and Max-Planck-Research-Group on Stem Cell Ageing, University of Ulm, Ulm, Germany.
authors: Patrick
authors: P
authors: Oeckl
authors: Annika
authors: A
authors: Scheffold
authors: André
authors: A
authors: Lechel
authors: K Lenhard
authors: KL
authors: Rudolph
authors: Boris
authors: B
authors: Ferger
mesh_terms: D015632:1-Methyl-4-phenyl-1,2,3,6-tetrahydropyridine / Q000494:pharmacology*; D015102:3,4-Dihydroxyphenylacetic Acid / Q000378:metabolism; D000818:Animals; D003342:Corpus Striatum / Q000187:drug effects / Q000378:metabolism; D004298:Dopamine / Q000031:analogs & derivatives / Q000378:metabolism*; D015259:Dopamine Agents / Q000494:pharmacology*; D006719:Homovanillic Acid / Q000378:metabolism; D008297:Male; D000090023:Metallothionein 3; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D009043:Motor Activity / Q000187:drug effects / Q000502:physiology; D009474:Neurons / Q000187:drug effects / Q000378:metabolism; D020734:Parkinsonian Disorders / Q000378:metabolism; D013378:Substantia Nigra / Q000187:drug effects* / Q000378:metabolism; D019098:Telomerase / Q000172:deficiency* / Q000235:genetics; D059506:Telomere Shortening; D014446:Tyrosine 3-Monooxygenase / Q000378:metabolism
chemical_list: D015259:Dopamine Agents; D000090023:Metallothionein 3; C000715430:Mt3 protein, mouse; D015102:3,4-Dihydroxyphenylacetic Acid; D015632:1-Methyl-4-phenyl-1,2,3,6-tetrahydropyridine; D014446:Tyrosine 3-Monooxygenase; D019098:Telomerase; C001746:3-methoxytyramine; D004298:Dopamine; D006719:Homovanillic Acid