Science Portrait: Prof. Luigi Zecca

This is a Science Portrait of Prof. Luigi Zecca, MD, Senior Researcher at the Institute of Biomedical Technologies-CNR, Milano, Italy. He will give a presentation at Fujita Health University, by Zoom, on Friday, November 26.

Prof. Zecca is an expert in the field of neuromelanins and metals in the human brain and their role in aging and diseases, most notably Parkinson’s disease. Prof. Zecca received his Chemistry Doctor and MD from the University of Milan (Italy). Since 1984, he has been a researcher in several functions at the Institute for Biomedical Technologies of Italy’s National Council of Research (CNR). There he has established the Unit of Brain Aging and Neurodegeneration. He has also done research at universities in other countries and currently is Visiting Professor of Neurobiology, Columbia University, New York.

His total number of publications is 164 and they have been cited ~14,200, with an H-index of 59. He was suggested as a speaker for our seminar by his friends and collaborators Prof. Kazumasa Wakamatsu and Prof. Shosuke Ito of Fujita Health University (Figs. 1 and 2). Therefore, below follows an introduction of Prof. Zecca by Prof. Wakamatsu. Below that, you can find a short CV of Prof. Zecca and his personal statement about his science (My Science).

We are very happy and honored that Prof. Zecca will tell us about his fascinating research on how the literally dark matter in the brain, neuromelanin, may both protect and harm us.

Introduction of Professor Luigi Zecca

(by Professor Kazumasa Wakamatsu)

Luigi Zecca MD is the leading scientist in the field of neuromelanins and metals in the human brain. He has worked with many collaborators on key aspects of neuromelanins regarding their structure, synthesis, interactions with metals, and functions/roles. In particular, he has shown that neuromelanins are ubiquitous in the human brain, occur in special autolysosomes, and accumulate in aging.

He is interested in a link between aging and neurodegeneration in Parkinson’s disease (PD). He is particularly interested in the neurodegenerative mechanisms of PD with an emphasis on the roles of neuromelanins and metals. He has shown that neuromelanins can be either protective or toxic, depending on the cellular context in brain aging and PD. He has found that neuromelanins released by degenerating neurons in PD can activate microglia, causing neuronal death and further release of neuromelanin. This establishes a vicious cycle of neuroinflammation and neurodegeneration and contributes to PD progression. He has described the paramagnetic and other physico-chemical properties of the neuromelanin-iron complex that were the fundamentals which allowed the development of magnetic resonance imaging of neuromelanins, which is nowadays used as a new tool for diagnosis of PD.

Currently, he is interested in the structure and pathways of neuromelanin autolysosomal organelles in neurons during aging. Furthermore, he is investigating contrast mechanisms associated with magnetic resonance imaging (MRI) of the neurodegeneration in PD and Alzheimer’s disease. 

He has published several papers on the isolation method and biochemical characterization of neuromelanin together with Emeritus Prof. Shosuke Ito and me. The first paper that the three of us co-authored was Structure and Function of Neuromelanin. In: Catecholamine Research: From Molecular Insights to Clinical Medicine published by Emeritus Prof. Toshiharu Nagatsu as an editor in 2002. Since then, we have been able to publish nine papers together. When he attended an international conference in Japan (Fig. 1), he visited our University. After that, in 2016, Emeritus Prof. Shosuke Ito and I visited his Milano’s laboratory to deepen our friendship. We are still conducting joint research on new themes.

 

CURRICULUM VITAE

 

EDUCATION

M.S.                                       Chemistry, University of Milan, Italy

Degree awarded in April 1974

M.D.                                       Medical School, University of Milan, Italy

Degree awarded in March 1995

 

PROFESSIONAL EXPERIENCE

1975-1983            Fellowship-Post Doctoral Training. University of Milano (Department of

Pharmacology), Italy

1984-2000            Researcher . Institute of Biomedical Technologies-CNR

2001-2007            Director of Research. Institute of Biomedical Technologies-CNR

2008-2015            Director of the Institute of Biomedical Technologies-CNR

1984-1985            Visiting scientist. Brookhaven National Laboratory, Upton – NY, USA

1992-1994            Visiting scientist. Dartmouth Medical School, Hanover – NH  (USA).

1999-2002            Visiting scientist. University of Wuerzburg. Germany.

2016 to date          Senior Researcher. Institute of Biomedical Technologies-CNR. Milano, Italy.

2018 to date          Steering Committee Member. National Institute of Research and Care of

Aging. Ancona. Italy

2018 to date          Visiting Professor of Neurobiology, Columbia University, New York, NY, USA.

2018 to date          Committee Member. Department of Biomedical Sciences. National Research

Council of Italy

 

RESEARCH INTERESTS

Neurochemistry — Neurobiology — Brain aging — Neuromelanin — Neuroinflammation —

Neurodegeneration — Parkinson’s disease — Magnetic resonance imaging (MRI)

 

PUBLICATIONS

Prof. Zecca has 164 publications, of which 25 in a journal with an impact factor >10. The most famous of those journals probably are: Trends in Neuroscience (2x of which 1x as first and corresponding author; PNAS (5x, of which 2x as first author and 1x as last author); The Lancet Neurology (corresponding author); Nature Communications; Nature Reviews Neuroscience (3x, of which 1x as first and corresponding author; Nature Biotechnology. For a more complete information about Prof. Zecca’s publications, see ORCID. For introducing himself to us, he has selected the below publications, which he categorized per topic:

 

Magnetic Resonance Imaging of neuromelanin and iron

Cassidy CM, Carpenter KM, Konova AB, Cheung V, Grassetti A, Zecca L, Abi-Dargham A, Martinez D, Horga G. Evidence for Dopamine Abnormalities in the Substantia Nigra in Cocaine Addiction Revealed by Neuromelanin-Sensitive MRI. Am J Psychiatry. 2020 Nov 1;177(11):1038-1047.

Betts MJ, Kirilina E, Otaduy MCG, Ivanov D, Acosta-Cabronero J, Callaghan MF, Lambert C, Cardenas-Blanco A, Pine K, Passamonti L, Loane C, Keuken MC, Trujillo P, Lüsebrink F, Mattern H, Liu KY, Priovoulos N, Fliessbach K, Dahl MJ, Maaß A, Madelung CF, Meder D, Ehrenberg AJ, Speck O, Weiskopf N, Dolan R, Inglis B, Tosun D, Morawski M, Zucca FA, Siebner HR, Mather M, Uludag K, Heinsen H, Poser BA, Howard R, Zecca L, Rowe JB, Grinberg LT, Jacobs HIL, Düzel E, Hämmerer D. Locus coeruleus imaging as a biomarker for noradrenergic dysfunction in neurodegenerative diseases. Brain. 2019 Sep 1;142(9):2558-2571.

Cassidy CM, Zucca FA, Girgis RR, Baker SC, Weinstein JJ, Sharp ME, Bellei C, Valmadre A, Vanegas N, Kegeles LS, Brucato G, Jung Kang U, Sulzer D, Zecca L, Abi-Dargham A, Horga G. Neuromelanin-sensitive MRI as a noninvasive proxy measure of dopamine function in the human brain. Proc Natl Acad Sci U S A. 2019 Feb 22. pii: 201807983.

Sulzer D, Cassidy C, Horga G, Kang UJ, Fahn S, Casella L, Pezzoli G, Langley J, Hu XP, Zucca FA, Isaias IU, Zecca L. Neuromelanin detection by magnetic resonance imaging (MRI) and its promise as a biomarker for Parkinson’s disease. NPJ Parkinsons Dis. 2018 Apr 10;4:11.

Isaias IU, Trujillo P, Summers P, Marotta G, Mainardi L, Pezzoli G, Zecca L, Costa A. Neuromelanin Imaging and Dopaminergic Loss in Parkinson’s Disease. Front Aging Neurosci. 2016 Aug 22;8:196.

 

Structure and synthesis of neuromelanis

Ferrari E, Capucciati A, Prada I, Zucca FA,  D’Arrigo G,  Pontiroli D, Bridelli MG, Sturini M, Bubacco L, Monzani E, Verderio C, Zecca L, Casella L. Synthesis, structure characterization and evaluation in microglia cultures of neuromelanin analogues suitable for modeling Parkinson’s disease. ACS Chem Neurosci. 2017 Mar 15;8(3):501-512.

Biesemeier A, Eibl O, Eswara S, Audinot JN, Wirtz T, Pezzoli G, Zucca FA, Zecca L, Schraermeyer U. Elemental mapping of Neuromelanin organelles of human Substantia Nigra: correlative ultrastructural and chemical analysis by analytical transmission electron microscopy and nano-secondary ion mass spectrometry. J Neurochem. 2016 Jul;138(2):339-53.

Wakamatsu K, Tabuchi K, Ojika M, Zucca FA, Zecca L, Ito S. Norepinephrine and its metabolites are involved in the synthesis of neuromelanin derived from the locus coeruleus. J Neurochem. 2015 Nov;135(4):768-76.

Engelen M, Vanna R, Bellei C, Zucca FA, Wakamatsu K, Monzani E, Ito S, Casella L, Zecca L. Neuromelanins of human brain have soluble and insoluble components with dolichols attached to the melanic structure. PLoS One. 2012;7(11):e48490.

 

Role of neuromelanins, iron and other agents in brain aging and Parkinson

Tokarew JM, El-Kodsi DN, Lengacher NA, Fehr TK, Nguyen AP, Shutinoski B, O’Nuallain B, Jin M, Khan JM, Ng ACH, Li J, Jiang Q, Zhang M, Wang L, Sengupta R, Barber KR, Tran A, Im DS, Callaghan S, Park DS, Zandee S, Dong X, Scherzer CR, Prat A, Tsai EC, Takanashi M, Hattori N, Chan JA, Zecca L, West AB, Holmgren A, Puente L, Shaw GS, Toth G, Woulfe JM, Taylor P, Tomlinson JJ, Schlossmacher MG. Age-associated insolubility of parkin in human midbrain is linked to redox balance and sequestration of reactive dopamine metabolites. Acta Neuropathol. 2021 May;141(5):725-754.

Capucciati A, Zucca FA, Monzani E, Zecca L, Casella L, Hofer T. Interaction of Neuromelanin with Xenobiotics and Consequences for Neurodegeneration; Promising Experimental Models. Antioxidants (Basel). 2021 May 21;10(6):824.

Sulzer D, Antonini A, Leta V, Nordvig A, Smeyne RJ, Goldman JE, Al-Dalahmah O, Zecca L, Sette A, Bubacco L, Meucci O, Moro E, Harms AS, Xu Y, Fahn S, Ray Chaudhuri K. COVID-19 and possible links with Parkinson’s disease and parkinsonism: from bench to bedside. NPJ Parkinsons Dis. 2020 Aug 20;6:18.

Zucca FA , Vanna R, Cupaioli FA, Bellei C, De Palma A, Di Silvestre D, Mauri P, Grassi S, Prinetti A, Casella L, Sulzer D, Zecca L. Neuromelanin organelles are specialized autolysosomes that accumulate undegraded proteins and lipids in aging human brain and are likely involved in Parkinson’s disease. NPJ Parkinsons Dis. 2018 Jun 5;4:17.

Zucca FA, Segura-Aguilar J, Ferrari E, Muñoz P, Paris I, Sulzer D, Sarna T, Casella L, Zecca L. Interactions of iron, dopamine and neuromelanin pathways in brain aging and Parkinson’s disease. Prog Neurobiol. 2017 Aug;155:96-119.

Cebrián C, Zucca FA, Mauri P, Steinbeck JA, Studer L, Scherzer CR, Kanter E, Budhu S, Mandelbaum J, Vonsattel JP, Zecca L, Loike JD, Sulzer D. MHC-I expression renders catecholaminergic neurons susceptible to T-cell-mediated degeneration. Nat Commun. 2014 Apr 16;5:3633.

Zucca FA, Basso E, Cupaioli FA, Ferrari E, Sulzer D, Casella L, Zecca L. Neuromelanin of the human substantia nigra: an update. Neurotox Res. 2014 Jan;25(1):13-23.

 

My Science

(written by Prof. Zecca)

From 1975-90 my interest was in pharmacokinetics and metabolism of benzodiazepines and non-steroidal anti-inflammatory drugs in humans and methods for determination of drugs in blood. I have also investigated the effect of benzodiazepines on gaba-ergic system and on morphine analgesia in rat. I have studied the mechanism of release and metabolism of nitric oxide in dopamine neurons and in human cerebrospinal fluid. I have developed radiopharmaceuticals for SPECT and PET imaging. From 1991 to date my interest has been in the structure, synthesis and roles of neuromelanin and metals in aging of human brain and Parkinson disease. I have described the protective and toxic roles of neuromelanin in different human brain regions. My interest has further expanded to contrast mechanism of neuromelanin and iron for MRI of neurodegeneration in Parkinson and Alzheimer. I have established the Unit of Brain Aging and Neurodegeneration at Institute of Biomedical Technologies-CNR. Milano, Italy.