Mortality, oxidative stress and tau accumulation during ageing in parkin null mice.
Young parkin null (pk-/-) mice have subtle abnormalities of behaviour, dopamine (DA) neurotransmission and free radical production, but no massive loss of DA neurons. We investigated whether these findings are maintained while ageing. Pk-/- mice have reduced life span and age-related reduced exploratory behaviour, abnormal walking and posture, and behaviours similar to those of early Parkinson's disease (PD), reduced number of nigrostriatal DA neurons and proapoptotic shifts in the survival/death proteins in midbrain and striatum. Contrary to young pk-/- animals 24-month-old pk-/- mice do not have compensatory elevation of GSH in striatum, glutathione reductase (GR) and glutathione peroxidase (GPx) activities are increased and catalase unchanged. Aged pk-/- mice accumulate high levels of tau and fail to up-regulate CHIP and HSP70. Our results suggest that aged pk-/- mice lack of the compensatory mechanisms that maintain a relatively normal DA function in early adulthood. This study could help to explain the effects of ageing in patients with genetic risks for Parkinson's disease.
Rodríguez-Navarro
Jose A
JA
Department of Neurobiology, Hospital Ramón y Cajal and CiBERNED, Madrid, Spain.
Casarejos
M José
MJ
Menéndez
Jaime
J
Solano
Rosa M
RM
Rodal
Izaskun
I
Gómez
Ana
A
Yébenes
Justo García de
JG
Mena
Maria A
MA
D000375:Aging / Q000378:metabolism*; D000818:Animals; D002452:Cell Count; D004195:Disease Models, Animal; D018450:Disease Progression; D004298:Dopamine / Q000378:metabolism; D005106:Exploratory Behavior; D008297:Male; D008636:Mesencephalon / Q000473:pathology; D051379:Mice; D018345:Mice, Knockout; D008818:Mice, Neurologic Mutants; D009043:Motor Activity / Q000235:genetics; D018384:Oxidative Stress / Q000235:genetics; D020734:Parkinsonian Disorders / Q000378:metabolism / Q000473:pathology / Q000503:physiopathology*; D011187:Posture; D013378:Substantia Nigra / Q000473:pathology; D015996:Survival Rate; D044767:Ubiquitin-Protein Ligases / Q000172:deficiency* / Q000235:genetics; D016875:tau Proteins / Q000378:metabolism*
D016875:tau Proteins; D044767:Ubiquitin-Protein Ligases; C111567:parkin protein; D004298:Dopamine