Head:

Dr. Maciej Figiel

Kalina Wiatr, MSc;

Piotr Piasecki, MSc;

Karolina Świtońska, MSc Eng.

Kalinowska Żaneta, MSc

Joanna Delimata, MSc

Rys.1

Rys.2

Rys.3

Rys.4

Rys.5

Rys.6

Rys.7

Rys.8

Highlights of the research profile:

1. new mechanisms of neurodegeneration, dna-dependent pathogenesis
2. new molecular targets for therapy
3. NeuroDEGENERATIVE disease = NeuroDEVELOPMENTAL disease?
4. cell therapy and modeling neurodegenerativ diseases in stem cells

Key words: 

Neurodegenerative disorders, neurodevelopmental disorders, mouse models, induced pluripotent stem cells, iPSC, SCA3, MJD, spinocerebellar ataxia type 3, Machado Joseph Disease, Huntington disease

Scientific profile:

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.
Another aim of the research is to investigate the pathogenesis of neurological disease along the developmental axis of pluripotent stem cells- neural stem cells-mature nerve cells. Along the axis we will examine deregulated proteins, mRNA, and changes in the chromatin. We will use induced pluripotent stem cell (iPSC) from patients suffering for polyQ diseases and the iPSC differentiated to neuronal stem cells and adult neurons and glial cells as well as new organoid technology.

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:

• General characterization of Ki91 SCA3 MJD knock-in mouse model
• Discovery of deregulated proteins, phosphoproteins, ubiquitinated proteins and mRNAs and splice forms in Ki91
• Behavioral investigation of the Ki91 mouse
• Generation of iPSC models of neurodegenerative diseases

Most important research achievements:

• The discovery of molecular phenotypes of early Huntington's Disease iPSC cells

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.

• Generation and characterization of the first mouse knock-out type 3 cerebellar ataxia type

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.

• Database of mouse models of polyglutamine diseases

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:

• Defining new neurodegeneration mechanisms using the first SCA3/MJD knock-in mouse model.; 2013/10/E/NZ4/00621

Selected publications:

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.
Switonski PM, Szlachcic WJ, Krzyzosiak WJ, Figiel M. A new humanized ataxin-3 knock-in mouse model combines the genetic features, pathogenesis of neurons and glia and late disease onset of SCA3/MJD. Neurobiol Dis. 2015 Jan;73:174-88.

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.

Switonski PM, Szlachcic WJ, Gabka A, Krzyzosiak WJ, Figiel M. Mouse models of polyglutamine diseases in therapeutic approaches: review and data table. Part II. Mol Neurobiol. 2012; 46(2):430-66.