The main objective of research in the field of neurodegenerative diseases associated with parkinsonism and dementia is to identify pathogenetic mechanisms to develop preventive, diagnostic and therapeutic interventions capable of recognize and counteracting, or slowing down, neuronal loss and symptoms characterizing the diseases. The over-activation of NF-?B has been observed in dying neurons of brains exposed to trauma and ischemia, as well as in brains of patients with Parkinson´s disease. By investigating the precise role of diverse NF-?B transcription factors (RelA, p50, c-Rel, p52 and RelB) in addressing neuronal cell fate, we found that activation of c-Rel can increase neuronal resilience to pathological noxae by regulating the expression of pro-survival MnSOD and Bcl-xL genes. We found that c-Rel deficient (c-rel-/-) mice develop a parkinsonian-like neuropathology with ageing. At 18 months of age, c-rel-/- mice exhibited a nearly 40% loss of dopaminergic neurons in the substantia nigra pars compacta (SNc), as assessed by TH and NeuN immunoreactivity. The nigral degeneration was accompanied by the loss of nigral dopaminergic terminals and significant reduction of dopamine (DA) and homovanillic acid (HVA) levels in the caudate putamen. The c-rel-/- mice exhibited increased expression of divalent metal transporter-1 and increased iron staining in both the SNc and striatum, in addition to marked immunoreactivity for fibrillary a-synuclein. Aged c-rel-/- brains exhibited increased microglial reactivity in the basal ganglia, but no astrocytic reaction. The behavioral examination of c-rel-/- mice revealed age-dependent deficits in locomotor and total activity, as well as in rotarod performance. Aged mice also displayed various gait-related deficits during a catwalk analysis that were reminiscent of bradykinesia and muscle rigidity. These data suggest that c-Rel may act as a regulator of the SNc resilience to ageing and c-rel-/- mice may represent a suitable model of age-associated PD.
Late-onset parkinsonism in NF-kB/c-Rel deficient mice
Pinna A;Morelli M;
2012
Abstract
The main objective of research in the field of neurodegenerative diseases associated with parkinsonism and dementia is to identify pathogenetic mechanisms to develop preventive, diagnostic and therapeutic interventions capable of recognize and counteracting, or slowing down, neuronal loss and symptoms characterizing the diseases. The over-activation of NF-?B has been observed in dying neurons of brains exposed to trauma and ischemia, as well as in brains of patients with Parkinson´s disease. By investigating the precise role of diverse NF-?B transcription factors (RelA, p50, c-Rel, p52 and RelB) in addressing neuronal cell fate, we found that activation of c-Rel can increase neuronal resilience to pathological noxae by regulating the expression of pro-survival MnSOD and Bcl-xL genes. We found that c-Rel deficient (c-rel-/-) mice develop a parkinsonian-like neuropathology with ageing. At 18 months of age, c-rel-/- mice exhibited a nearly 40% loss of dopaminergic neurons in the substantia nigra pars compacta (SNc), as assessed by TH and NeuN immunoreactivity. The nigral degeneration was accompanied by the loss of nigral dopaminergic terminals and significant reduction of dopamine (DA) and homovanillic acid (HVA) levels in the caudate putamen. The c-rel-/- mice exhibited increased expression of divalent metal transporter-1 and increased iron staining in both the SNc and striatum, in addition to marked immunoreactivity for fibrillary a-synuclein. Aged c-rel-/- brains exhibited increased microglial reactivity in the basal ganglia, but no astrocytic reaction. The behavioral examination of c-rel-/- mice revealed age-dependent deficits in locomotor and total activity, as well as in rotarod performance. Aged mice also displayed various gait-related deficits during a catwalk analysis that were reminiscent of bradykinesia and muscle rigidity. These data suggest that c-Rel may act as a regulator of the SNc resilience to ageing and c-rel-/- mice may represent a suitable model of age-associated PD.I documenti in IRIS sono protetti da copyright e tutti i diritti sono riservati, salvo diversa indicazione.
