LATE-ONSET PARKINSONISM AND PREMOTOR PATHOLOGY IN NF-KB/C-REL-DEFICIENT MICE

Nigrostriatal dopamine (DA) neuron degeneration, synaptic dysfunctions and neuroinflammation are among the key pathological features of Parkinson?s disease (PD). NF-kB factors are considered cardinal players in the progression of the neurodegenerative process, with dual effect on inflammation and apoptosis. While NF-kB/RelA factor is responsible for the commencement of apoptotic gene expression, NF-kB/c-Rel factor promotes transcription of anti-apototic genes, MnSOD, Bcl-xL and UCP4. Aim: To investigate possible age-associated neurodegeneration in c-rel-/- mice. Methods: WT and c-rel-/- mice were analyzed at 2, 12 and 18 months of age for their motor behavior, brain neurochemistry and pathology Results: At 18 months, c-rel-/- mice develop DA neuronal loss in substantia nigra pars compacta (SNc) with accumulation of aggregated alpha-synuclein and iron, microglia activation and a motor dysfunction. Motor deficits, occurring as hypo-motility and gait disorders, were responsive to L-DOPA administration. More recently we have found that a pathology characterized by alpha-synuclein accumulation in the dorsal nucleus of vagus and locus coeruleus, as well as striatal loss of dopamine transporter, is already present at a premotor age (12 months), making these mice a suitable model to investigate therapeutic approaches for early intervention in PD. Furthermore, blood mononuclear cells (PBMC) of selected PD patients display significantly reduced c-Rel activity. Conclusions: c-Rel factor is a regulator of SNc resilience to aging. Mice deficient for c-Rel represent an innovative animal model to study either premotor pathology and pathological progression of PD. It discloses a possible new diagnostic and therapeutic target deserving further investigation in PD patients.