marek napieralaAssociate Professor

Research Areas
Molecular mechanisms of repeat expansion diseases


Research Interests

Our laboratory is focused on studying molecular mechanisms of repeat expansion diseases and discoveries leading to potential treatment of these diseases. Since the first report in 1991 of the CGG repeat expansion leading to fragile X syndrome, more than 20 other human diseases caused by a mutation in unstable repeat sequences have been identified (Figure 1). This group includes common neurological and neuromuscular inherited disorders such as myotonic dystrophy type 1 (DM1), as well as rare diseases such as spinocerebellar ataxias (SCAs). While the vast majority of these diseases are caused by expansions of trinucleotide repeat sequences, expansions of other repeat tracts, including tetra-, penta- and hexanucleotide repeats, have also been identified (Figure 1). In the unaffected population, repeat tracts are short and stable, whereas in affected individuals the tracts become longer and frequently become somatically unstable.

Pathogenic repeat sequences can be found in any region of a gene, including coding sequences, 5’ and 3’ UTRs, as well as introns (Figure 1). A correlation can be observed between the location and the size of the expansions, with a greater propensity for expansion associated with non-coding repeat tracts. The largest observed expansions can span several thousand repeats. In the majority of cases, the repeats elongate from one generation to the next, which is associated with increasing severity of disease symptoms and decreasing age of onset - a phenomenon that has been termed anticipation. 

Figure 1
Figure 1. Repeat expansion disease (Polak et al. Biofactors 2013

In the past we have worked on projects directly related to CTG repeat expansions in myotonic dystrophy type I, CGG expansion in fragile X syndrome, CAG expansions in Huntington’s disease, and CCTG repeats in myotonic dystrophy type II. In the past 10 years the major focus of our research is Friedreich’s ataxia (FRDA). It is a severe neurodegenerative disease caused by transcriptional repression induced by expanded GAA repeats located in intron 1 of the FXN gene (Figure 2). FRDA is  the most common inherited ataxia in humans, with ~ 1 in 100 people carrying a mutation in FXN gene and the overall population frequency reaching 1 in 30000 to 50000. The majority of FRDA patients are homozygous for large expansions of GAA repeat sequences in intron 1 of the FXN gene while a small fraction of patients are compound heterozygotes with an expanded GAA repeat sequence in one FXN allele and a missense or nonsense mutation in the other. Patients homozygous for GAA expansion are deficient for the mitochondrial protein frataxin, a protein involved in iron-sulfur cluster synthesis. Characteristic symptoms of FRDA include discoordination, slurred speech, muscle weakness, peripheral neuropathy, and cardiomyopathy.  At the present time there is no effective treatment for FRDA.  Friedreich’s ataxia patients always express a detectable level of FXN, ranging from ~5 – 35% of levels that can be detected in a control cohort. Importantly, the protein coding sequence of FXN is unaffected in the vast majority of FRDA patients, suggesting that upregulation of endogenous FXN expression could be an effective therapy. 

Figure2
Figure 2. Homozygous expansion of GAA repeats in the first intron of the FXN gene located on chromosome 9 leads to downregulation of the frataxin expression. FXN mRNA levels are reduced to ~ 50% of the unaffected controls in heterozygous, asymptomatic carriers of the GAA expansion on a single FXN allele. Expression of frataxin is inversely correlated with number of GAA repeats.

Our comprehensive program encompasses studies related to:
1. Mechanism of transcription silencing induced by expanded GAA repeats in FRDA gene.
2. Therapeutic strategies aimed to reactivate transcription of the FXN gene
3. Genome editing as a regenerative therapy approach to Friedreich’s ataxia
4. Mitochondrial changes in FRDA cells.
5. Biomarkers of Friedreich’s ataxia.
6. Molecular phenotype of FRDA neuronal and cardiac cells derived from induced pluripotent stem cells.
7. Effect of point mutations on frataxin functions and disease phenotype

Education

Graduate School
Ph.D., Institute of Bioorganic Chemistry Polish Academy of Sciences, Poznan, Poland

Postdoctoral Fellowship
Institute of Biosciences and Technology, Texas A&M University, Houston

Contact

Office
Shelby Biomedical Research Building
Room 706
1825 University Blvd.
Birmingham, AL 35294-2182

Phone
(205) 975-5320

Email
mnapiera@uab.edu


Friedreich’s Ataxia Primary Fibroblast Repository

Please use this link in conjunction with the form below to place your order.

Fibroblast Request Form

In collaboration with Dr. David Lynch from Children’s Hospital of Philadelphia we established a bank of ~50 FRDA patient fibroblasts. Please fill out the form below, and we will contact you with a confirmation of your request.
Name(*)
Invalid Input

University/Company(*)
Invalid Input

Cell Line(s) Requested(*)
Invalid Input

Short Description of Planned Research(*)
Invalid Input

Shipping Address(*)
Invalid Input

Email Address(*)
Invalid Input

Phone(*)
Invalid Input

FEDEX Account Number(*)
Invalid Input

(*)
Invalid Input

Submit

Committed to exploring new frontiers in basic and translational research.

The Department of Biochemistry and Molecular Genetics is an integral part of the vibrant biomedical research community at the University of Alabama at Birmingham (UAB). UAB ranks among the top public institutions of higher education in terms of research and training awards. Research conducted by the faculty, staff, and students of the Department of Biochemistry and Molecular Genetics is currently supported by more than $7.1 million per year in extramural, investigator-initiated grants.

Research

The Department of Biochemistry and Molecular Genetics carries out cutting-edge basic and translational research. Research strengths in the department includes cancer biology, chromatin and epigenetic signaling, metabolism and signaling, regulation of gene expression, structural biology, DNA synthesis and repair, and disease mechanisms.

Education

Graduate students and postdoctoral fellows in the Department of Biochemistry and Molecular Genetics are trained to carry out hypothesis-driven research using advanced research techniques. This training will prepare our graduates for a career in not just biomedical research, but also in other diverse fields that require critical thinking. Our faculty also proudly trains professional (MD, DDS, & DO) students, as well as undergraduate students at UAB.