Discovering the potential of NMP
The Türker Lab explores how neuronal membrane proteasomes regulate brain signaling and contribute to neurodegenerative diseases like Huntington’s, aiming to uncover novel mechanisms and therapeutic targets.
“Proteasomes are more complex than appreciated”
Seth. S. Margolis
Project 1. Changes in cell surface proteome in Huntington’s disease
To date, no study has comprehensively investigated global membrane protein dynamics in HD models, even though significant alterations in specific membrane proteins, such as major modulators of neurotransmission (AMPA and NMDA receptors), have been linked to HD pathology. We aim to compile the first large dataset of global membrane proteome changes in the striatum of a transgenic HD mouse model (R6/2 mice), providing a valuable resource for future research and other research groups.
Project 2. Regulation of NMP in R6/2 Huntington’s disease mouse model
Our primary aim is to rigorously investigate NMP biology across distinct brain regions in HD mice of varying ages, each exhibiting distinct molecular pathology and HD phenotypes. The use of different brain regions will enable us to learn and correlate the link between aggregate formation and NMP dynamics since aggregation will not be evenly distributed across all brain regions. Also, we aim to analyze the NMP-dependent changes in brain pathology by tracking the behavioral and molecular disease markers. We investigate changes in behavioral phenotypes of disease, such as clasping, weight loss, anxiety-like behavior as well as molecular and structural markers following NMP inhibition.
Project 3. NMP dynamics in Huntington’s disease in vitro models
We use the HD cell culture model (STHdhQ111/Q111) to compare the NMP dynamics at the cellular level to healthy neurons and investigate the role of neuronal membrane proteasome (NMP) inhibition in HD phenotypes.
The STHdhQ111/Q111 cell line is derived from striatal neurons of knock-in mice homozygous for 111 CAG repeats in the huntingtin (HTT) gene, similar to the genetic mutation seen in HD patients and R6/2 mice. These cells exhibit critical HD phenotypes, including impaired intracellular trafficking, mitochondrial dysfunction, and altered neuronal viability, and mutant huntingtin protein (mHtt) aggregation under proteotoxic stress.
Project 4. Investigation of proteasome and NMP biology using microfluidics platforms, with a focus on HD models
This proeject aims to investigate the role of NMPs in specific neuronal compartments using advanced microfluidic technology. The key objectives are to (i) evaluate how NMP inhibition impacts neural transmission by reconstructing a cortico-hippocampal network on a microfluidic platform, (ii) develop an HD model-on-a-chip to study the role of NMP in disease progression, and (iii) explore the therapeutic potential of NMP-derived bioactive peptides. This research has the potential to provide insights into NMP-dependent signaling pathways in neurons and open new avenues for therapeutic strategies in neurodegenerative diseases, including HD.
Project 2. Regulation of NMP in R6/2 Huntington’s disease mouse model
Our primary aim is to rigorously investigate NMP biology across distinct brain regions in HD mice of varying ages, each exhibiting distinct molecular pathology and HD phenotypes. The use of different brain regions will enable us to learn and correlate the link between aggregate formation and NMP dynamics since aggregation will not be evenly distributed across all brain regions. Also, we aim to analyze the NMP-dependent changes in brain pathology by tracking the behavioral and molecular disease markers. We investigate changes in behavioral phenotypes of disease, such as clasping, weight loss, anxiety-like behavior as well as molecular and structural markers following NMP inhibition.
Project 1. Changes in cell surface proteome in Huntington’s disease
To date, no study has comprehensively investigated global membrane protein dynamics in HD models, even though significant alterations in specific membrane proteins, such as major modulators of neurotransmission (AMPA and NMDA receptors), have been linked to HD pathology. We aim to compile the first large dataset of global membrane proteome changes in the striatum of a transgenic HD mouse model (R6/2 mice), providing a valuable resource for future research and other research groups.
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