Late-onset Parkinsonism in NFκB/c-Rel-deficient mice.
Activation of the nuclear factor κB/c-Rel can increase neuronal resilience to pathological noxae by regulating the expression of pro-survival manganese superoxide dismutase (MnSOD, now known as SOD2) and Bcl-xL genes. We show here that c-Rel-deficient (c-rel(-/-)) mice developed a Parkinson's disease-like neuropathology with ageing. At 18 months of age, c-rel(-/-) mice exhibited a significant loss of dopaminergic neurons in the substantia nigra pars compacta, as assessed by tyrosine hydroxylase-immunoreactivity and Nissl staining. Nigral degeneration was accompanied by a significant loss of dopaminergic terminals and a significant reduction of dopamine and homovanillic acid levels in the striatum. Mice deficient of the c-Rel factor exhibited a marked immunoreactivity for fibrillary α-synuclein in the substantia nigra pars compacta as well as increased expression of divalent metal transporter 1 (DMT1) and iron staining in both the substantia nigra pars compacta and striatum. Aged c-rel(-/-) mouse brain were characterized by increased microglial reactivity in the basal ganglia, but no astrocytic reaction. In addition, c-rel(-/-) mice showed age-dependent deficits in locomotor and total activity and various gait-related deficits during a catwalk analysis that were reminiscent of bradykinesia and muscle rigidity. Both locomotor and gait-related deficits recovered in c-rel(-/-) mice treated with l-3,4-dihydroxyphenylalanine. These data suggest that c-Rel may act as a regulator of the substantia nigra pars compacta resilience to ageing and that aged c-rel(-/-) mice may be a suitable model of Parkinson's disease.
Department of Biomedical Sciences and Biotechnologies, University of Brescia and National Institute of Neuroscience, 25123 Brescia, Italy.
Cristina
C
Baiguera
Manuela
M
Alghisi
Annalisa
A
Pinna
Arianna
A
Bellucci
Maria Antonietta
MA
De Luca
Lucia
L
Frau
Micaela
M
Morelli
Rosaria
R
Ingrassia
Marina
M
Benarese
Vanessa
V
Porrini
Michele
M
Pellitteri
Giuseppe
G
Bertini
Paolo Francesco
PF
Fabene
Sandra
S
Sigala
Maria Grazia
MG
Spillantini
Hsiou-Chi
HC
Liou
Pier Franco
PF
Spano
Marina
M
Pizzi
D000375:Aging / Q000235:genetics* / Q000378:metabolism; D000818:Animals; D002452:Cell Count; D003342:Corpus Striatum / Q000378:metabolism / Q000473:pathology; D004298:Dopamine / Q000378:metabolism; D059290:Dopaminergic Neurons / Q000378:metabolism / Q000473:pathology*; D006719:Homovanillic Acid / Q000378:metabolism; D051379:Mice; D018345:Mice, Knockout; D009043:Motor Activity / Q000235:genetics; D016328:NF-kappa B / Q000235:genetics* / Q000378:metabolism; D020734:Parkinsonian Disorders / Q000235:genetics* / Q000378:metabolism / Q000473:pathology; D013378:Substantia Nigra / Q000378:metabolism / Q000473:pathology*; D051844:alpha-Synuclein / Q000378:metabolism
D016328:NF-kappa B; D051844:alpha-Synuclein; D004298:Dopamine; D006719:Homovanillic Acid