Molecular mechanisms of neurodegeneration

Molecular mechanisms of neurodegeneration

Current work in the lab focusses on the role and pathological mechanisms of toxic protein aggregation in neurodegenerative diseases, as well as cellular defense systems that cope with the aggregates.

Section of a Huntington’s disease mouse brain with inclusions (red) in striatal cells (green). Nuclei are labeled in blue.

A common feature of many neurodegenerative diseases such as Alzheimer’s disease, Parkinson’s disease, Huntington’s disease and amyotrophic lateral sclerosis, is the deposition of misfolded amyloid-like proteins in nerve cells and sometimes in the surrounding extracellular matrix. Although it is clear that aggregating proteins cause damage to the neurons, the molecular mechanisms of aggregate toxicity remain largely unknown.

We investigate the effects of aggregating proteins in primary neuronal cultures and in vivo in mouse models of neurodegenerative diseases. In cooperation with the departments of Ulrich Hartl, Matthias Mann and Wolfgang Baumeister (MPI of Biochemistry), we take a multidisciplinary approach to characterize the composition of amyloid-like aggregates, their localization in the cell and their impact on neuronal function and survival.

We currently focus on Huntington’s disease (HD), the most common hereditary neurodegenerative disorder, caused by a CAG repeat expansion in the Huntingtin gene. This genetic defect results in the production of the aggregation-prone polyglutamine (polyQ)-expanded mutant Huntingtin (mHtt) protein.

Repeated two-photon calcium imaging in the cortex of HD mice at different disease stages

One potential mechanism of aggregation toxicity involves interactions of the aggregating species with multiple essential cellular proteins, resulting in the sequestration of those proteins within the aggregates. To investigate the composition of mHtt inclusion bodies, in collaboration with the lab of Matthias Mann we have performed an extensive proteomic screen in a mouse model of HD at various disease stages. Several brain regions that differ in their susceptibility to HD were analyzed in order to understand the region specificity that is characteristic of neurodegenerative diseases (Hosp, Gutierrez-Angel, et al., 2017).

A number of interesting candidates from the proteomic screen are being pursued to explore their role in aggregate toxicity and assess their disease-modifying potential.

Accumulation of artificial amyloid-like aggregates in cortical neurons of a transgenic mouse

Disturbance of neuronal activity patterns is an early sign of neurodegeneration that precedes cell death. With the help of chronic in-vivo two photon imaging, we monitor neuronal activity in the cortex of HD mouse models before and after the onset of symptoms to understand mHtt-induced changes in neuronal function and intercellular communication.

In addition, we are interested in uncovering common molecular mechanisms relevant for different neurodegenerative diseases. We are comparing the effects of various natural disease-causing proteins in primary neurons. The architecture of the aggregates and their interactions with cellular organelles are being explored by cryo-electron tomography in collaboration with the Baumeister lab.

As an additional approach to address common mechanisms of aggregate toxicity, we are working with rationally designed amyloid-like proteins. We have generated transgenic mouse lines that can be used to express these amyloid-like proteins in different cell populations in the brain. We are characterizing these mice by histological, biochemical and behavioral assays to investigate the impact of aggregation on brain structure and function.

Proteostasis sensor (green) reveals disturbance of cellular defense mechanisms in primary neurons by forming inclusions.

A number of cellular defense mechanisms (proteostasis mechanisms) exist to clear damaged proteins from the cells. However, these defense strategies sometimes fail, leading to the accumulation of misfolded proteins. In a collaborative project with the Hartl lab, we study the impact of aggregation on the cellular defense against toxic proteins. We have generated transgenic reporter mice in which the activity of those defense components can be visualized and measured. By crossing these reporter mice to disease models, we can monitor the status of the cellular defense systems at different stages of disease.

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