Neurodegeneration

A part of our group focuses on pharmacological and toxicological research in the areas of neurodegeneration. New cell models and endpoints are being established and used to obtain information relevant for human health and safety without animal experiments. Four major pathological events are observed in many disease, including Alzheimer’s disease (AD) and Parkinson’s disease (PD): protein aggregation, inflammation, oxidative stress and mitochondrial dysfunction. We are interested in their modulation by drugs, in high content screening of cellular alterations and in the chemical biology involved in protein modifications. We are interested in the interplay of factors that trigger degeneration (ref. 4) and examine specific mechanisms relevant to Parkinson’s disease (e.g. synuclein biochemistry, ref. 3) or Alzheimer’s disease (amyloid production, ref. 5)

To study and model key mechanisms of neurodegenerative diseases in cell cultures of human neurons, we have developed co-cultures of neurons and glial cells (ref. 1). To deal with the complexity of degeneration processes, we also use multi-omics approaches to obtain data on a systems wide level and to model pivotal processes (ref. 2)

Example references:

  1. Efremova L, Chovancova P, Adam M, Gutbier S, Schildknecht S, Leist M (2017) Switching from astrocytic neuroprotection to neurodegeneration by cytokine stimulation.

    Arch Toxicol, 91, 231-246

  2. Krug AK, Gutbier S, Zhao L, Kullmann C, Pöltl D, Ivanova V, Förster S, Jagtap S, Meiser J, Leparc G, Schildknecht S, Adam M, Hiller K, Farhan H, Brunner T, Hartung T, Sachinidis A, Leist M (2014) Transcriptional and metabolic adaptation of human neurons to the mitochondrial toxicant MPP+.         
    Cell Death Disease 5, e1222

  3. Robotta M, Gerding HR, Vogel A, Hauser K, Schildknecht S, Karreman C, Leist M, Vinod Subramaniam V, Drescher M. (2014) Alpha-Synuclein binds to the inner membrane of mitochondria in an alpha-helical conformation.

    ChemBioChem 15, 2499-2502

  4. Schildknecht S, Gerding HR, Karreman C, Drescher M, Lashuel HA, Outeiro TF, Di Monte DA, Leist M (2013) Oxidative and nitrative alpha synuclein modifications and proteostatic stress: implications for disease mechanisms and interventions in synucleinopathies          

    J Neurochem 125, 491-511.

  5. Scholz D, Chernyshova Y, Leist M (2013). Control of A-beta release from human neurons by differentiation status and RET signaling.     

    Neurobiol Aging 34, 184-199