Genetic mutations linked to Parkinson's disease differentially control nucleolar activity in pre-symptomatic mouse models

Abstract

Genetic mutations underlying neurodegenerative disorders impair ribosomal DNA (rDNA) transcription suggesting nucleolar dysfunction as a novel pathomechanism in polyglutamine diseases and in certain forms of amyotrophic lateral sclerosis/frontotemporal dementia. Here, we investigated nucleolar activity in pre-symptomatic digenic models of Parkinson's disease (PD) modeling the multifactorial etiology of this disease. To this end, we analyzed a novel mouse model mildly overexpressing the mutant human-A53T-alpha-synuclein (hA53T-SNCA/PARK1) in a PTEN-induced kinase 1 (PINK1/PARK6) knock-out background and mutant mice lacking both DJ-1/PARK7 and PINK1/PARK6. We showed that overexpressed human-A53T-alpha-synuclein localizes in the nucleolus. Moreover, these mutants show a progressive reduction of rDNA transcription linked to a reduced mouse lifespan. On the contrary in DJ-1/PINK1 double knock-out (DKO) mice rDNA transcription is preserved. mRNA levels of the nucleolar transcription initiation factor-IA (TIF-IA) decrease in substantia nigra of PD patients. Because loss of TIF-IA, as a tool to mimic nucleolar stress, increases oxidative stress and because DJ-1 and PINK1 mutations result in higher vulnerability to oxidative stress, we further explored the synergism between these PD-associated genes and impaired nucleolar function. By the conditional ablation of TIF-IA gene, we blocked ribosomal RNA (rRNA) synthesis in adult dopaminergic neurons in a DJ-1/PINK1 DKO background. However, the early phenotype of these triple knock-out mice was similar to those mice exclusively lacking TIF-IA. These data sustain a model in which DJ-1/PINK1 loss does not impair nucleolar activity in a pre-symptomatic stage. This is the first study that analyzes nucleolar function in digenic PD models. We can conclude that at least in these models the nucleolus is not as severely disrupted as previously shown in DA neurons from PD patients and neurotoxin-based PD mouse models. The results also show that early increase in rDNA transcription and nucleolar integrity may represent specific homeostatic responses in these digenic pre-symptomatic PD models.