Team: Metabolic and neurodegenerative diseases

Leader: Ana Messias

Members:

• Stephanie Ortiz Collazos, Postdoctoral fellow
• Stefan Hempfling, Master's student
• Franziska Scholz, Bachelor's student

The main research emphasis in the Messias team is the study of the basic molecular mechanisms involved in several human metabolic and neurodegenerative diseases. In particular, we are interested in understanding how proteins execute their native function and how it is altered by disease, by looking at the details of their 3D structure in an integrative structural biology approach combined with biochemical and biophysical techniques. This information is then used for the rational development of novel drugs to ameliorate the disease conditions.

Current research area focus on genetic and acquired metabolic diseases, in particular linked to diabetes and obesity. We unravel and exploit novel molecular features of the function of regulatory proteins in insulin- and leptin-based signalling, namely of protein tyrosine phosphatases (PTPs), and use it in structure-based drug discovery to identify and develop novel allosteric compounds in diabetes and obesity.

A second focus of research is on rare inherited diseases causative of Neurodegeneration with Brain Iron Accumulation (NBIA). Among NBIA diseases, we study MPAN (Mitochondrial Protein Associated Neurodegeneration), a fatal disease without treatment, with onset in infancy which is caused by mutations on C19orf12, a protein with unknown biological function. By using an approach using structural biology, biochemistry, biophysics and combining it with proteomics and cellular biology, we aim to understand the basic molecular and cellular mechanism of C19orf12 and uncover how mutations cause MPAN. The ultimate goal is to develop personalized drugs that will extend and improve life of MPAN patients.

Selected Publications:

1. Detection and quantification of the anti-obesity drug celastrol in murine liver and brain.
   De Angelis M, Schriever SC, Kyriakou E, Sattler M, Messias AC, Schramm KW, Pfluger PT.
   Neurochem Int. 2020 Jun; 136:104713. doi: 10.1016/j.neuint.2020.104713.
   Epub 2020 Mar 6. PMID: 32151623

 

2. Structural Insight into IAPP-Derived Amyloid Inhibitors and Their Mechanism of Action.
   Niu Z, Prade E, Malideli E, Hille K, Jussupow A, Mideksa YG, Yan LM, Qian C, Fleisch M, Messias AC, Sarkar R, Sattler M, Lamb DC, Feige MJ, Camilloni C, Kapurniotu A, Reif B.
   Angew Chem Int Ed Engl. 2020 Mar 27;59(14):5771-5781. doi: 10.1002/anie.201914559.
   Epub 2020 Jan 28. PMID: 31863711

 

3. Celastrol Promotes Weight Loss in Diet-Induced Obesity by Inhibiting the Protein Tyrosine Phosphatases PTP1B and TCPTP in the Hypothalamus.
   Kyriakou E, Schmidt S, Dodd GT, Pfuhlmann K, Simonds SE, Lenhart D, Geerlof A, Schriever SC, De Angelis M, Schramm KW, Plettenburg O, Cowley MA, Tiganis T, Tschöp MH, Pfluger PT, Sattler M, Messias AC.
   J Med Chem. 2018 Dec 27; 61(24):11144-11157. doi: 10.1021/acs.jmedchem.8b01224.
   Epub 2018 Dec 7. PMID: 30525586

 

4. Fluorescent blood-brain barrier tracing shows intact leptin transport in obese mice.
   Harrison L, Schriever SC, Feuchtinger A, Kyriakou E, Baumann P, Pfuhlmann K, Messias AC, Walch A, Tschöp MH, Pfluger PT.
   Int J Obes (Lond). 2019 Jun;43(6):1305-1318. doi: 10.1038/s41366-018-0221-z.
   Epub 2018 Oct 3. PMID: 30283080

 

5. Celastrol-Induced Weight Loss Is Driven by Hypophagia and Independent From UCP1.
   Pfuhlmann K, Schriever SC, Baumann P, Kabra DG, Harrison L, Mazibuko-Mbeje SE, Contreras RE, Kyriakou E, Simonds SE, Tiganis T, Cowley MA, Woods SC, Jastroch M, Clemmensen C, De Angelis M, Schramm KW, Sattler M, Messias AC, Tschöp MH, Pfluger PT.
   Diabetes. 2018 Nov;67(11):2456-2465. doi: 10.2337/db18-0146.
   Epub 2018 Aug 28. PMID: 30158241

 

6. Mutations in PPCS, Encoding Phosphopantothenoylcysteine Synthetase, Cause Autosomal-Recessive Dilated Cardiomyopathy.
   Iuso A, Wiersma M, Schüller HJ, Pode-Shakked B, Marek-Yagel D, Grigat M, Schwarzmayr T, Berutti R, Alhaddad B, Kanon B, Grzeschik NA, Okun JG, Perles Z, Salem Y, Barel O, Vardi A, Rubinshtein M, Tirosh T, Dubnov-Raz G, Messias AC, Terrile C, Barshack I, Volkov A, Avivi C, Eyal E, Mastantuono E, Kumbar M, Abudi S, Braunisch M, Strom TM, Meitinger T, Hoffmann GF, Prokisch H, Haack TB, Brundel BJJM, Haas D, Sibon OCM, Anikster Y.
   Am J Hum Genet. 2018 Jun 7;102(6):1018-1030. doi: 10.1016/j.ajhg.2018.03.022.
   Epub 2018 May 10. PMID: 29754768

 

7. Structural Characterization of LRRK2 Inhibitors.
   Gilsbach BK, Messias AC, Ito G, Sattler M, Alessi DR, Wittinghofer A, Kortholt A.
   J Med Chem. 2015 May 14;58(9):3751-6. doi: 10.1021/jm5018779.
   Epub 2015 May 1. PMID: 25897865

 

Previous and Current Funding:

Michael J. Fox Foundation (US), NBIA-DA (US), Association NBIA Poland (Poland)