Research Focus: nucleolar stress in neuronal homeostasis in health and disease
The nucleolus, the site where rRNA synthesis and ribosome biogenesis take place, is a fundamental sensor and a mediator of the response to stress conditions. For example, increased oxidative stress, DNA damage, neurotrophin withdrawal, mutant mRNAs and proteins downregulate rRNA transcription with consequent disruption of nucleolar integrity - a condition known as nucleolar stress (Figure 1) (reviewed by Parlato and Kreiner, 2013). Although nucleolar stress is associated with neurodegenerative disorders such as Alzheimer´s, Parkinson´s (PD) and Huntington´s disease (HD), its impact on neuronal activity and survival has not been systematically explored. Yet, the identification of early cellular and molecular alterations triggered by nucleolar stress could advance our understanding of disease progression and the design of effective therapeutic strategies.
Our main research focuses on the question how nucleolar stress steers neuroprotective and neurotoxic mechanisms in healthy and pathological contexts in particular in neurodegenerative disorders.
To dissect context-specific mechanisms responding to nucleolar stress, we developed novel mouse models characterized by impaired rRNA synthesis in distinct neurons (Parlato et al, 2008). We provided the first evidence that nucleolar stress in dopaminergic neurons that are affected in PD, leads to mitochondrial and oxidative damage, slowly progressive degeneration of substantia nigra neurons and motor impairment - hallmarks of the human disease (Rieker et al, 2011).
To further characterize the mechanistic link between nucleolar dysfunction and neurodegeneration, we focused as a model on the role of nucleolar stress in the progression of HD, a fatal inherited disorder in the huntingtin gene leading primarily to impaired control of voluntary movements. Remarkably, in this disease rRNA transcription is strongly downregulated by mutant huntingtin. Moreover, we showed that in dopaminoceptive neurons of the striatum, mainly affected in HD, nucleolar stress triggers neuroprotective mechanisms dependent on downregulation of the mammalian target of rapamycin (mTOR) and induction of autophagy (Kreiner et al, 2013). These findings support the importance of nucleolar stress in the disease onset and progression.
Using a combination of biochemical, histological and behavioral approaches we are currently investigating:
- Whether increased inhibition of rRNA transcription can accelerate (or delay) neurodegeneration in models of HD.
- The role of genes triggered by the early response to nucleolar stress in survival of neuronal models of HD.
- The effects of nucleolar stress on translation of specific mRNAs in vivo.
The spectrum of techniques we adopt includes: mouse genetics, motor behavioral tests, immunohistological analysis optimized to detect in situ rRNA transcription, nucleolar and oxidative stress, gene expression and translation analysis (mRNA, microRNA and translated mRNA profiling) in tissues and in neuronal cultures.
Our results could support the development of therapeutic approaches targeting nucleolar activity in HD and possibly in other neurodegenerative disorders.
R. Parlato* and H. Bierhoff. Role of nucleolar dysfunction in neurodegenerative disorders: a game of genes? AIMS Molecular Science, 2015; 2(3): 211-224. (Special Issue: Molecular Mechanisms of Neurodegenerative Diseases)
R. Parlato* and B. Liss. How Parkinson´s disease meets nucleolar stress. BBA-Molecular basis of disease, 2014; 1842(6):791-97.
A. Kiryk, K. Sowodniok, G. Kreiner, J. Rodriguez-Parkitna, A. Sönmez, T. Gorkiewicz, H. Bierhoff, M. Wawrzyniak, A. Janusz, B. Liss, W. Konopka, G. Schütz, L. Kaczmarek, R. Parlato*. Impaired rRNA synthesis triggers homeostatic responses in hippocampal neurons. Frontiers in Cellular Neuroscience, 2013; 7:207
G. Kreiner, H. Bierhoff, M. Armentano, J. Rodriguez Parkitna, K. Sowodniok, L. Bonfanti, B. Liss, G. Schütz, I. Grummt, R. Parlato*. A neuroprotective phase precedes striatal degeneration upon nucleolar stress. Cell Death Differ, 2013; 20:1455-1464. (See also Editorial by JD Erickson and NG Bazan in Cell Death Differ, 2013; 20:1435-1437)
R. Parlato* and G. Kreiner. Nucleolar activity in neurodegenerative diseases: a missing piece of the puzzle? J Mol Med, 2013; 91:541-7. (Featured online under the “Key Scientific Articles” section of Global Medical Discovery [ISSN1929-8536])
A. Domanskyi, C. Geißler, I. Vinnikov, H. Alter, A. Schober, M. Vogt, P. Gass, R. Parlato and G. Schütz. Pten ablation in adult dopaminergic neurons is neuroprotective in mouse models of Parkinson's disease. FASEB J 2011; 25:2898-2910.
C. Rieker, D. Engblom, G. Kreiner, A. Domanskyi, A. Schober, S. Stotz, M. Neumann, X. Yuan, I. Grummt, G. Schütz and R. Parlato. Nucleolar disruption in dopaminergic neurons leads to oxidative damage and parkinsonism through repression of mTOR signaling. J Neurosci, 2011; 31:453-60. (F1000.com/9005956, rating 8)
R. Parlato, G. Kreiner, G. Erdmann, C. Rieker, S. Stotz, E. Savenkova, S. Berger, I. Grummt and G. Schütz. Activation of an endogenous suicide response due to perturbation of rRNA synthesis leads to neurodegeneration in mice. J Neurosci. 2008; 28: 12759-64.
(* Corresponding author)