Group PD Dr. Uwe Ueberham

RNA pattern as a biomarker for neurodegenerative diseases and functional characterization of long non protein coding RNAs in Alzheimer’s disease

Recent studies suggest that various neurodegenerative diseases, e.g. Alzheimer’s disease (AD), are characterized by substantial disturbances of RNA metabolism in the brain. The underlying process is an early event in AD pathogenesis, and is therefore of specific interest for the development of reliable and early diagnostic tests.

In human brain RNA is characterized by stronger heterogeneity and diversity compared to other organs and tissues. Accordingly, in the project the relationship of RNA diversity and neurodegeneration is examined to establish new tools for the development of RNA-based diagnostic approaches. 

Moreover, as non protein coding RNAs often have specific critical function in the regulation of differentiation processes, the project is also analysing RNAs, consisiting of coding and long non coding sequences to explore their role for neuronal plasticity  and the pathogenesis of neurodegenerative diseases. Interactions between long non coding RNAs (lncRNA) and DNA-, RNA- or protein binding partners are examined by specific assays, eg. Electromobility shift assays (EMSA) or by surface plasmon resonance analysis (SPR).

The following questions of special interest: (1) Are lncRNAs specifically involved into pathophysiologic desregulation in AD brain? (2) What are relevant molecular targets of those lncRNAs? (3) What is the mechanism of the participating lncRNA sequences and what impact do these RNAs have on neuronal cell death?​

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Development of innovative approaches to treat Alzheimer’s disease and related diseases – A new concept for a somatic gene therapy

Alzheimer’s disease (AD) and vascular dementia (VD) are the main reasons for mental disturbances in higher aged people. AD and VD are characterized by neuronal cell death, which is triggered by an uncoordinated re-entry of neurons into cell cycle and a subsequent incomplete DNA replication process.

For AD, we could confirm a direct relationship between neuronal death and DNA-replication.  Therefore, the control of cell cycle proteins in terminally differentiated neurons is an immediate therapeutic approach for AD treatment. Accordingly, in the project we further develop our therapeutic concept of neuroprotection to slow down or even prevent neuronal cell death by neuron-specific somatic gene therapy.  The approach will be extended to other neurodegenerative diseases and could be relevant for non-neuronal diseases exhibiting pathological cell cycle activation, e.g. cancer or atherosclerosis. 

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Function of Smad proteins in neurodegenerative processes in brain ​

Smad proteins are transcription factors of the canonical TGFbeta/BMP superpathway. They are involved in brain development as well as in maintanance of brain specific differentiation processes.

Recent studies suggest, that the fuctional spectrum of Smads is more extensive and also includes their participation into neurodegenerative processes in human brain. 

Until now reasons of neurodegenerative diseases are only partly understood. Experiments show, that activation of cell cycle proteins is a substantial part of AD, which contributes to neuronal cell loss. 

A disturbed regulation of neuronal cell cycle proteins is also involved in the development of other neurodegenerative disease, e.g. Parkinson’s disease, Amyotrophic lateral sclerosis or stroke. 

Factors triggering disturbed cell cycle activation in neurons, are barely examined. A candidate, suggested to contribute causatively to neurodegeneration in brain, is Transforming Growth Factor beta (TGFbeta). TGFbeta can control proliferation, differentiation and cell division in various cell types and can immediately can affect activity and expression of cell cycle proteins. Thereby, TGFbeta can use intracellular signalling via Smad proteins, which in turn are regulated by receptor-mediated phosphorylation. However, the role of neuronal Smad proteins is only limited investigated and their function for the cell cycle activation process in not understood in neurons. 

In healthy brain phosphorylated Smads are localized in neuronal nuclei. In AD brain, we could detect for the first time a massive disturbance of neuronal Smad localization. The nuclear Smad content was reduced significantly, while cytoplasmic Smad-containing vesicles were detectable or Smads closely linked to neurofibrillar structures were identified. Wir assume that nuclear Smad loss causes neuronal dedifferentiation, uncontrolled activation of cell cycle proteins or even contributes to deregulation of synaptic and extrasynaptic proteins. In the project we examine this questions by biochemical, molecular biological, cell biological and immunohistochemical methods.

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Examination of chromosomal variations and neuronal mosaic-aneupolidy in Alzheimer’s disease

Previously, we have detected in the human central nervous system chromosomal "copy number variations" (CHROM-CNV), which are due to loss or gain of complete chromosoms or parts of chromosomes and which were identified in healthy brains and in AD (Alzheimer’s disease) brains.

In sporadic AD, increased neuronal cell death is associated to neurons containing CHROM-CNV. However, investigations suggest, that neurons with CHROM-CNV are a common phenomenon in the adult central nervous system. 

Although during brain development neurons with CHROM-CNV are removed by apoptosis, several of those probably escape this selection mechanism and persist in the adult brain. A now delayed starting apoptosis of affected neurons can contribute to neurodegenerative diseases of “late-onset” typus. Each of those neurons now runs through an individual apoptosis process. Accordingly, in pyramidal cells in AD brain aneuploid or polyploid characteristics indicate abnormal DNA replication. Number, frequency and distribution pattern of aneuploid neurons in human brain, the participation of different chromosoms and the consequences for brain function and diseases of central nervous systems are nearly completely unknown. 

The main goal of the projct is the analysis of numeric chromosomal aberration in hippocampal and cortical nerve cells in AD brain. To this end single cell studies will be carried out and combined with comprehensive sequencing methods to gain inside into pathomechanisms of neuronal cell death in AD.  ​

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