Research Groups

Portrait Jared Sterneckert

Jared Sterneckert

iPS Cells and Neurodegenerative Disease

Previous and Current Research

Neurodegenerative diseases such as Parkinson’s disease (PD) and amyotrophic lateral sclerosis (ALS) cause significant suffering. Aging is one of the biggest risk factors for these diseases, and, as a result, the number of patients having neurodegenerative diseases is rapidly increasing as people live longer – so much so that you likely know someone that is affected. Basic science studies have identified possible drug candidates to prolong neuronal survival in patients. However, these drug candidates have almost universally failed in clinical trials. As a result, physicians can do very little to help patients once diagnosed. Critical questions are:

  • Why do neurons degenerate?
  • Why is it age dependent?
  • How can we extend neuronal survival?
  • How do we improve the success of clinical translation in order to better help patients?

A critical ingredient to answering these questions is to be able to study human neurons. This is not trivial. Until recently, human neurons were almost completely unavailable. Instead, transformed cell lines such as HeLa were used. However, it is now apparent that drugs found using transformed cell lines haven’t been very successful in patients. Induced pluripotent stem cells (iPSCs) offer a revolutionary alternative. Using reprogramming, we can directly generate iPSCs from skin cells of a patient. iPSCs can undergo immortal self-renewal as well as differentiate into functional neurons, meaning that they can provide a theoretically limitless supply of neurons that can be used to study the same disease that affected the donating patient. Using gene editing, we can correct disease mutations, make knockouts, and insert reporters. We can perform drug screening to identify effective drugs. For example, we recently generated a model of ALS using FUS-eGFP reporter, which we used to identify FDA-approved drugs that rescued the disease. We have teamed up with pharmaceutical partners as well as clinicians so that these studies can move from the bench to patients and back again to the laboratory for validation.

Future Projects and Goals
  • Unlike HeLa cells, neurons have axons. Since axons are the first to degenerate in patients, we are generating models of axon degeneration using iPSC-derived neurons. In particular, we are interested in the effects of aging and disease-causing mutations on axons.
  • Together with the Lead Discovery Center GmbH, we are screening small molecules for their ability to protect neurons, including axons, against neurodegeneration.
  • There are two major difficulties in developing new treatments for ALS and PD patients. First, the diseases begin many years before diagnosis, and, second, we often don’t know if the drug in question is having the effect on neurons that we want it to have. Biomarkers are critical to addressing both issues. Using iPSCs, and in cooperation with clinical partners, we aim to identify and validate candidate biomarkers to enable earlier diagnosis and facilitate clinical translation of novel therapeutics.
Methodological and Technical Expertise
  • Reprogramming to generate iPSC lines.
  • Directed differentiation of iPSCs
  • Gene editing
  • Small molecule screening
Selected Publications

Maharana S, Wang J, Papadopoulos DK, Richter D, Pozniakovsky A, Poser I, Bickle M, Rizk S, Guillén-Boixet J, Franzmann T, Jahnel M, Marrone L, Chang YT, Sterneckert J, Tomancak P, Hyman AA, Alberti S
RNA buffers the phase separation behavior of prion-like RNA binding proteins.
Science. 2018 May 25;360(6391):918–921 (2018)

Marrone L, Bus C, Schöndorf D, Fitzgerald JC, Kübler M, Schmid B, Reinhardt P, Reinhardt L, Deleidi M, Levin T, Meixner A, Klink B, Glatza M, Gloeckner CJ, Gasser T, Sterneckert J
Generation of iPSCs carrying a common LRRK2 risk allele for in vitro modeling of idiopathic Parkinson’s disease.
PLoS One. 2018 Mar 7;13(3):e0192497 (2018)

Marrone L, Poser I, Casci I, Japtok J, Reinhardt P, Janosch A, Andree C, Lee HO, Moebius C, Koerner E, Reinhardt L, Cicardi ME, Hackmann K, Klink B, Poletti A, Alberti S, Bickle M, Hermann A, Pandey UB, Hyman AA, Sterneckert JL
Isogenic FUS-eGFP iPSC Reporter Lines Enable Quantification of FUS Stress Granule Pathology that Is Rescued by Drugs Inducing Autophagy.
Stem Cell Reports. 2018 Feb 13;10(2):375–389 (2018)

Reinhardt P, Schmid B, Burbulla LF, Schöndorf DC, Wagner L, Glatza M, Höing S, Hargus G, Heck SA, Dhingra A, Wu G, Müller S, Brockmann K, Kluba T, Maisel M, Krüger R, Berg D, Tsytsyura Y, Thiel CS, Psathaki OE, Klingauf J, Kuhlmann T, Klewin M, Müller H, Gasser T, Schöler HR, Sterneckert J
Genetic Correction of a LRRK2 Mutation in Human iPSCs Links Parkinsonian Neurodegeneration to ERK-Dependent Changes in Gene Expression.
Cell Stem Cell. 12(3):354–67 (2013)

Höing S, Rudhard Y, Reinhardt P, Stehling M, We G, Peiker C, Böcker A, Glatza M, Slack M, Sterneckert J*, Schöler HR*
Discovery of inhibitors of microglial neurotoxicity acting through multiple mechanisms using a stem cell-based phenotypic assay.
Cell Stem Cell. 11(5):620–632 (2012) [*co-corresponding authors]

CV

since September 2014
Group Leader, CRTD

2010–2014
Project Group Leader, Max Planck Institute for Molecular Biomedicine (Münster, Germany)

2006–2009
Postdoctoral Research Fellow, Max Planck Institute for Molecular Biomedicine (Hans R. Schöler; Münster, Germany)

1998–2005
Ph.D. Johns Hopkins University (John D. Gearhart; Baltimore, MD, USA)

Contact

Center for Regenerative Therapies Dresden
TU Dresden
Fetscherstraße 105
01307 Dresden

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