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 that nucleolar dysfunction could be 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) that model the multifactorial aetiology of this disease. To this end, we analysed a novel mouse model mildly overexpressing mutant human α-synuclein (hA53T-SNCA) in a PTEN-induced kinase 1 (PINK1/PARK6) knockout background and mutant mice lacking both DJ-1 (also known as PARK7) and PINK1. We showed that overexpressed hA53T-SNCA localizes to the nucleolus. Moreover, these mutants show a progressive reduction of rDNA transcription linked to a reduced mouse lifespan. By contrast, rDNA transcription is preserved in DJ-1/PINK1 double knockout (DKO) mice. mRNA levels of the nucleolar transcription initiation factor 1A (TIF-IA, also known as RRN3) decrease in the substantia nigra of individuals with PD. 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, we blocked ribosomal RNA (rRNA) synthesis in adult dopaminergic neurons in a DJ-1/PINK1 DKO background. However, the early phenotype of these triple knockout mice was similar to those mice exclusively lacking TIF-IA. These data sustain a model in which loss of DJ-1 and PINK1 does not impair nucleolar activity in a pre-symptomatic stage. This is the first study to analyse 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 the early increase in rDNA transcription and nucleolar integrity may represent specific homeostatic responses in these digenic pre-symptomatic PD models.

DNA damage and repair in Parkinson's disease: Recent advances and new opportunities

“…Although the presence of α‐syn in the nucleus has been controversial, recent studies have consistently found evidence of nuclear α‐syn (Ma et al, 2014; Pinho et al, 2019; Siddiqui et al, 2012; Zhou, Xu, Mi, Ueda, & Chan, 2013). In mice overexpressing human A53T α‐syn in a PINK1 null background, mutant α‐syn was also reported to be in the nucleus (Evsyukov et al, 2017). Nuclear α‐syn can bind DNA and when overexpressed can cause DNA single‐strand breaks and double‐strand breaks, particularly under oxidative conditions (Vasquez et al, 2017).…”

Back and to the Future: From Neurotoxin‐Induced to Human Parkinson's Disease Models

“…The mice exhibited progressive degeneration of dopaminergic neurons, reduced striatal dopamine levels, and behavioral abnormalities (Rieker et al., ). In contrast to PD patients and toxin‐induced mouse PD models, nucleolar integrity was not affected by DJ‐1/PINK1 double knockout, highlighting the value of the TIF‐IA conditional knockout model to study PD‐related nucleolar dysfunction (Evsyukov et al., ). The utility of TIF‐IA/DAT‐CreET2 mice for pre‐clinical drug testing has recently been proven by the study showing a neuroprotective effect of reboxetine, a selective noradrenaline reuptake inhibitor, on dopaminergic neurons (Kreiner et al., ).…”

Crosstalk between NF-κB and Nucleoli in the Regulation of Cellular Homeostasis

“…High levels of nucleolar activity are a hallmark of cancer and contribute to tumor growth by allowing de-regulated protein synthesis and uncontrolled activity of nucleolar cell growth/death pathways [ 16 , 82 ]. Changes in nucleolar morphology and function are also common in age related neurodegenerative disorders and increasing evidence suggests that this dysfunction contributes to disease progression, as well as the normal aging process [ 17 , 18 , 46 , 83 , 84 ]. Similarly, dysregulated NF-κB activity is common in cancer, neurodegenerative disorders and aging and contributes to the progression of these diseases/aging through promotion of a chronic inflammatory environment and modulation of genes that regulate cell growth/death [ 40 , 85 , 86 ].…”