Department of Molecular Neurobiology (DMN)
Piotr Piasecki, MSc;
Karolina Świtońska, MSc Eng.
Highlights of the research profile:
Neurodegenerative disorders, neurodevelopmental disorders, mouse models, induced pluripotent stem cells, iPSC, SCA3, MJD, spinocerebellar ataxia type 3, Machado Joseph Disease, Huntington disease
The long-term research objective of the Department of Molecular Neurobiology is to identify new mechanisms of neurodegeneration and in particular to identify earliest molecular mechanisms related to neurodevelopment. In addition the research objective is to explore these molecular mechanisms in search of effective treatments for neurodegenerative diseases through the discovery of new therapeutic targets. The diseases constituting a valid model of neurodegeneration investigated in the Department are Huntington's disease and spinocerebellar ataxia type 3 (SCA3 / MJD), which are polyglutamine (polyQ) diseases.
The aim of the research currently conducted in the Department is to identify new biomolecules with altered activation or expression in a KI91 knock-in mouse model of SCA3/MJD. Identification of these biomolecules will facilitate the discovery of new neurodegenerative mechanisms and likely aid the discovery of universal therapeutic targets involved in the pathogenesis of neurological diseases. The results obtained recently revealed altered protein and mRNA that show a relationship of SCA3 mechanisms to the processes occurring in Alzheimer's disease, Huntington's, Parkinson's and ALS.
Neurological disease are characterized by the loss of nerve cells in the central nervous system. The aim of the Department will also be investigation of the cell therapy for neurological diseases and the identification of the mechanisms associated with effective cell therapy.
Current research activity:
Most important research achievements:
We identified molecular early signs/phenotypes of Huntington neurological disease in pluripotent stem cells and have demonstrated that one of these molecular alterations, namely the deregulated expression of p53 is also present after the differentiation of iPSC to neural stem cells stage. Our research also demonstrates that the decreased expression of p53 can be reversed by stable expression of RNA interference reagents targeting the mutant huntingtin.
We generated a mouse knock-in SCA3/MJD model by introducing patient human ataxin-3 cDNA containing 91 CAG repeats while deleting several Atxn3 mouse exons and introns. The resulting Ki91 mice contain hybrid humanized Atxn3 gene and express human mutant ataxin-3 in the brain and peripheral tissues. We also generated animals in which we increased the number of CAG repeats to 110, also including two alleles of the mutant gene (homozygous version). At present, phenotypes of homozygous mice are during intensive characterization process. An additional important goal is to further "improve" the model to prepare a strain of mice with more severe symptoms of neurodegenerative disease and to be suitable for preclinical studies to test new drugs.
We have created a database of mouse models of polyglutamine diseases that contains over 120 different polyQ mouse models. The database includes data on the course of neurodegenerative disease such as detailed mouse phenotypes as well as therapeutic approaches involving various drugs and genetic modifications that have been tested on these models. The database is available at: http://conyza.man.poznan.pl/
Current research projects:
Wiatr K, Szlachcic WJ, Trzeciak M, Figlerowicz M, Figiel M. Huntington disease as neurodevelopmental disorder and early phenotypes of the disease in stem cells. Mol Neurobiol. 2017;
Szlachcic WJ, Switonski PM, Kurkowiak M, Wiatr K, Figiel M. Mouse polyQ database: a new online resource for research using mouse models of neurodegenerative diseases. Mol Brain. 2015 Oct 29;8(1):69.
Szlachcic WJ, Switonski PM, Krzyzosiak WJ, Figlerowicz M, Figiel M. Huntington disease iPSCs show early molecular changes in intracellular signaling, the expression of oxidative stress proteins and the p53 pathway. Dis Model Mech. 2015 Sep;8(9):1047-57. doi: 10.1242/dmm.019406.
Figiel M, Szlachcic WJ, Switonski PM, Gabka A, Krzyzosiak WJ. Mouse models of polyglutamine diseases: review and data table. Part I. Mol Neurobiol. 2012; 46(2):393-429.
Figiel M, Krzyzosiak WJ, Switonski PM, Szlachcic WJ. (2015). Chapter 64: Mouse Models of SCA3 and Other Polyglutamine Repeat Ataxias. In Movement Disorders, Second Edition. Ed. LeDoux M. ISBN: 9780124051959 DOI: 10.1016/B978-0-12-405195-9.00064-0