NCoE Recruits

Valentina Fedele, PhD, postdoctoral fellow

I started my postdoc position in Patrik Brundin's lab last February. I was involved in research addressing the elucidation of the mechanisms of cellular apoptosis in human placenta during my PhD and also during my trainee researcher in MRC, Leicester UK. During the three years of working as Career Development Fellow in MRC, Leicster UK, I have been focused on the characterization of the mitochondrial proteome HtrA2 knockout animals as well as biochemical characterization of mitochondrial stress pathways, more specifically looking at the role of the serine protease HtrA2 in mitochondrial stress. Because Htra2 is the gene that has been associated with PD and HtrA2 KO mice develop parkinsonian features, my research has been also focused on the role of mitochondria in neuronal survival pathways. During my postdoc I will study deficits and the underlying mechanisms of intraneuronal trafficking of mitochondria and neurotransmitter-containing synaptic vesicular organelles in models of Parkinson's disease and Huntington's disease.

Srikanth Ranganathan, PhD, postdoctoral fellow

I recently joined Dr. Brundin's laboratory. My research project focuses on pathogenetic mechanisms in Huntington's disease (HD) models and pharmacological therapy. This Nesu project will be in collaboration with Lundbeck A/S at Copenhagen. Prior to being a NCoE fellow, I did my post-doctoral fellowship under the mentorship of Dr. Kenneth Fischbeck's at the National Institute of Neurological Disorders and Stroke (NINDS/NIH, MD, USA). I investigated the effect of polyglutamine expansion mutation in androgen receptor on mitochondria in spinal and bulbar muscular atrophy. I joined NINDS after my doctoral work in Dr. Robert Bowser's laboratory in the Department of Cellular and Molecular Pathology at the University of Pittsburgh (Pittsburgh, PA, USA). During the doctoral work, I investigated alterations in G(1) to S phase cell cycle regulators and apoptotic proteins in ALS motor neurons. I was also responsible for initiating and developing the mass spectrometry-based proteomic study (SELDI-TOF) for ALS biomarker discovery.

Christa Maynard, PhD, postdoctoral fellow

I started as a post-doc in the laboratory of Nico Dantuma, at the Karolinska Institute in 2004. Here I have been investigating the functionality of the ubiquitin proteasome system (UPS) of protein degradation in Huntington's disease. Huntington's disease (HD) is caused by expansion of a polyglutamine encoding CAG tract in the huntingtin gene, resulting in a mutant protein with an enhanced tendency to aggregate. The huntingtin inclusions found in HD brain are highly ubiquitylated, suggesting failure of the cell to degrade this difficult substrate. Whether the accumulation of ubiquitinylated huntingtin is a cause, a consequence or an epiphenomenon of the pathogenic process in HD remains heavily debated and is the focus of this study.

To monitor UPS function directly in mouse brain, our laboratory has generated a transgenic mouse expressing a fluorescent UPS-substrate that allows us to detect UPS impairment in precisely the cells the impairment is occurring in, via the accumulation of fluorescence. I have crossed these UPS reporter mice with transgenic mouse models of HD to monitor UPS function during HD pathogenesis. In collaboration with Patrik Brundin, we are conducting essential control experiments, to determine whether alterations in reporter levels could be caused by transcriptional dysregulation in the double transgenic mice. Our results to date have revealed no global impairment of UPS function in HD mice, but preliminary results suggest a possible adaptation of the cells proteolytic machinery to chronic expression of mutant huntingtin. In collaboration with Patrik Brundin, we will also examine the capacity of neurons to accumulate reporter upon proteasome impairment using organotypic and acute brain slices in the reporter mice.

Annakaisa Haapasalo, PhD, research specialist

I am a research specialist in Professor Hilkka Soininen's Alzheimer Research group at University of Kuopio. I also closely collaborate with the Functional Genetics group of Research Director Mikko Hiltunen with whom I share supervision of three doctoral students. As NCoE collaboration with Professor Nico Dantuma at Karolinska Institute, we have launched a project "Assessing the role of novel Alzheimer's disease (AD) -associated protein ubiquilin 1 in protein aggregation and ubiquitin-proteasome system". Ubiquilin 1, has recently been shown to be genetically and functionally linked to AD, is a ubiquitin-like protein regulating proteasomal degradation of various proteins, including AD-associated presenilin 1 (PS1). As proteasomal dysfunction plays a role in AD pathogenesis, even minor changes in ubiquilin 1 expression or function may affect levels of multiple proteins. Therefore, we investigate how overexpression or knockdown of ubiquilin 1 affects aggregation and degradation of PS1 and other proteins when proteasomal function is compromised. My background is in neurobiology. I received my PhD at the University of Kuopio in 2003 on neurotrophin receptors. Thereafter, I worked as a postdoctoral fellow in 2004-2006 at Massachusetts General Hospital and Harvard Medical School in Boston, where I became interested in the molecular pathogenesis of AD and the role of PS/gamma-secretase in proteolytic processingof proteins. I am presently continuing these studies here in Kuopio.

Linda Møllersen, PhD, postdoctoral fellow

I started my post.doc at Arne Klungland's lab in May 2006. The aim of my study is to investigate whether DNA repair could affect the propagation of the dynamic mutations in triplet repeat diseases such as Huntington's disease. The structure-specific flap endonuclease 1 (Fen1) cleaves flaps generated by strand displacement during replication and repair. Our lab has made knock-in mice models with mutant Fen1. In particular, mice with the Fen1 E160D mutation (Glu ? Asp in the active site resulting in 20% activity) have been crossed with mice transgenic for Huntington's disease. Preliminary results show small effects on somatic and intergenerational triplet repeat expansions. In collaboration with P. Brundin, pathological examinations will be performed. By using mathematical calculations on raw data of fragment analysis, two modes of somatic triplet expansion in have been identified (in preparation). In future studies we will investigate whether Fen1 G242D mutant mice could have a larger effect on triplet repeat instability, since this has been shown in yeast.

CHristian Hansen, PhD, postdoctoral fellow

I joined Professors Patrik Brundins lab December 2008. Prior to this I did my PhD study (defended Jan. 2008) and postdoctoral work in Professor Tommy Anderssons lab at CRC, Malmö (Lund University) up until I joined the present lab. In Professor Anderssons lab I studied the role of Wnt-5a and DARPP-32 in breast cancer cell signaling and cell migration. 

My goal at NCoE is to study EGFP-a-synuclein transgenic mice by 2-photon microscopy to gain knowledge on the aggregation process and toxicity of human -a-synuclein in vivo. For this purpose I will also inject recombinant a-synuclein oligomers and fibrils into the mice. Dysregulation of a-synuclein expression and activity is a hallmark of Parkinsons disease. Therefore, a better understanding of how this molecule works in vivo constitute a major challenge and more knowledge in this area could lead to identification of novel ways to treat Parkinsons disease.  The project will be done in collaboration with Lundbeck A/S and P.H. Jensen at University of Århus.