Parkinson’s disease (PD) is characterized by an inevitable loss of dopaminergic cells.However, examination of human brain tissues revealed that noradrenergic cell loss in the region of the locus coeruleus (LC) may proceed and may be even greater than dopaminergic degeneration. AIM(S): The aim of this study was to determine whether genetically evoked, selective loss of LC noradrenergic neurons in a progressive manner may negatively influence the dopaminergic system. Our mice models have progressive degeneration of the noradrenergic system, based on deletion of the gene Rrn3 encoding transcription factor TIF-IA, which is essential for the regulation of rRNA synthesis. METHOD(S): First, we applied the conditional inactivation of the Rrn3 by the Cre-loxP system expressing Cre recombinase under DBH promoter. TIF‑IADBHCre mice revealed ptosis, reduced locomotor activity, and a shortened life span associated with enhanced expression of various neurodegenerative markers within the dopaminergic system, including upregulation of micro- and astroglia, pro-inflammatory proteins, and enhanced level of oxidative stress. To limit mutations to the CNS, in a second model a Cre-dependent lentiviral vector carrying the Rrn3 deletion created by the CRISPR/Cas9 system was directly delivered to LC of DBHCre mice. RESULTS: Our construct was first successfully tested in vitro on primary dopamine neurons followed by in vivo stereotactic application. This approach seems to be successful as, in preliminary data, we observed the disintegration of nucleoli in transduced noradrenergic neurons in LC, which is the determinant of the functional impairment of the targeted TIF‑IA. CONCLUSIONS: To-date, there are no experimental studies on possible long-term negative impacts of progressive noradrenergic degeneration on other neurotransmitter systems, despite the clinically observed concomitant loss of SN/VTA and LC neurons in PD. If we provide additional evidence, mice with ongoing neurodegeneration of LC neurons may became a valuable tool for studying the presymptomatic phase of PD.