Late-onset Parkinsonism in NFκB/c-Rel-deficient mice

被引：71

作者：

Baiguera, Cristina ^{[1
,2
]}

Alghisi, Manuela ^{[1
,2
]}

Pinna, Annalisa ^{[3
,4
,5
]}

Bellucci, Arianna ^{[1
,2
]}

De Luca, Maria Antonietta ^{[4
,5
]}

Frau, Lucia ^{[3
,4
,5
]}

Morelli, Micaela ^{[3
,4
,5
]}

Ingrassia, Rosaria ^{[1
,2
]}

Benarese, Marina ^{[1
,2
]}

Porrini, Vanessa ^{[1
,2
]}

Pellitteri, Michele ^{[6
]}

Bertini, Giuseppe ^{[6
]}

Fabene, Paolo Francesco ^{[6
]}

Sigala, Sandra ^{[1
,2
]}

Spillantini, Maria Grazia ^{[7
]}

Liou, Hsiou-Chi ^{[8
]}

Spano, Pier Franco ^{[1
,2
,9
]}

Pizzi, Marina ^{[1
,2
,9
]}

机构：

[1] Univ Brescia, Dept Biomed Sci & Biotechnol, I-25123 Brescia, Italy

[2] Natl Inst Neurosci, I-25123 Brescia, Italy

[3] Inst Neurosci, Natl Res Council, I-09124 Cagliari, Italy

[4] Univ Cagliari, Dept Biomed Sci, I-09124 Cagliari, Italy

[5] Univ Cagliari, Natl Inst Neurosci, I-09124 Cagliari, Italy

[6] Univ Verona, Dept Neurol Neuropsychol Morphol & Motor Sci, I-37134 Verona, Italy

[7] Univ Cambridge, Dept Clin Neurosci, Brain Repair Ctr, Cambridge CB2 0PY, England

[8] Cornell Univ, Weill Med Coll, Dept Immunol, New York, NY 10065 USA

[9] IRCCS San Camillo Hosp, Venice, Italy

来源：

BRAIN | 2012年 / 135卷

关键词：

Parkinson's disease; NF kappa B/c-Rel; alpha-synuclein; motor impairments; L-DOPA; HIGH-FREQUENCY STIMULATION; MGLU5 RECEPTOR AGONISTS; FACTOR C-REL; DOPAMINERGIC-NEURONS; TRANSCRIPTION FACTOR; ALPHA-SYNUCLEIN; SUBTHALAMIC NUCLEUS; CEREBRAL-ISCHEMIA; ALZHEIMER-DISEASE; SUBSTANTIA-NIGRA;

D O I：

10.1093/brain/aws193

中图分类号：

R74 [神经病学与精神病学];

学科分类号：

100204 [神经病学];

摘要：

Activation of the nuclear factor kappa B/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 a-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.

引用

页码：2750 / 2765

页数：16

共 65 条

[1]

c-Rel, an NF-κB family transcription factor, is required for hippocampal long-term synaptic plasticity and memory formation [J].