TY - JOUR
T1 - Brain tyrosinase overexpression implicates age-dependent neuromelanin production in Parkinson’s disease pathogenesis
AU - Carballo-Carbajal, Iria
AU - Laguna, Ariadna
AU - Romero-Giménez, Jordi
AU - Cuadros, Thais
AU - Bové, Jordi
AU - Martinez-Vicente, Marta
AU - Parent, Annabelle
AU - Gonzalez-Sepulveda, Marta
AU - Peñuelas, Núria
AU - Torra, Albert
AU - Rodríguez-Galván, Beatriz
AU - Ballabio, Andrea
AU - Hasegawa, Takafumi
AU - Bortolozzi, Analía
AU - Gelpi, Ellen
AU - Vila, Miquel
N1 - Funding Information:
This work was supported by funds from the Fondo de Investigación Sanitaria-Instituto de Salud Carlos III (FIS-ISCIII, Spain)-European Regional Development Fund (FEDER, E.U.) (PI13/01897, to M.V.), Parkinson’s U.K. (to M.V.), Ministry of Economy and Competitiveness (MINECO, Spain) (SAF2016-77541-R and RTC-2014-2812-1, to M.V.), The Michael J. Fox Foundation (U.S.A) (ID15291, to M.V.), La Caixa Banking Foundation (Health Research Project HR17-00513, to M.V.) and CIBERNED (to M.V.). In addition, the Authors would like to acknowledge additional support from the Fundación Tatiana Pérez de Guzmán el Bueno (Spain, to A.L.), Michael J. Fox Foundation (U.S.A.) (ID11580, to A.L.), MINECO (SAF2016-75797-R, to A.Bo.) and FIS-ISCIII-FEDER (PI15/01937 to J.B. and PI13/01390 to A.Bo.). A.L. was the recipient of a post-doctoral fellowship Beatriu de Pinós (2013 BP-DGR B 00043) from the Agència de Gestió d’Ajuts Universitaris i de Recerca (AGAUR, Spain) with co-funding from the Marie Curie COFUND program (E.U.) and a postdoctoral contract SAF2015-73997-JIN from MINECO (Spain) with co-funding from FEDER (E.U.). N.P. is the recipient of a predoctoral fellowship FPI (BES-2017-080191) from MINECO (Spain). A.T. is the recipient of a pre-doctoral fellowship PFIS (FI14/00613) from the FIS-ISCIII (Spain). We are grateful to: E. Ruiz-Bronchal (IIBB-CSIC-IDIBAPS, Barcelona, Spain) for technical assistance in the performance of microdialysis/HPLC experiments; the Neurological Tissue Bank of the Biobanc-Hospital Clinic-IDIBAPS (Barcelona, Spain) for human data and sample procurement; S. Lope-Piedrafita (UAB, Barcelona, Spain) for technical assistance in the performance of MRI experiments in rodents; the Unit 20 of CIBER in Bioengineering, Biomaterials & Nanomedicne (CIBER-BBN) at the VHIR (Barcelona, Spain) for assistance in histological processing; D. Sebastián and A. Zorzano (IRB-PCB, Barcelona, Spain) for assistance in the SeaHorse mitochondrial respirometry experiments; I. Fariñas (University of Valencia-CIBERNED) for providing aSyn-deficient mice; A. Rovira (Neuroradiology section, Vall d’Hebron Hospital, Barcelona, Spain) for providing the MRI image from a human control subject and S. Dovero (University of Bordeaux, France) for drawing the rodent brain atlas illustrations.
PY - 2019/12/1
Y1 - 2019/12/1
N2 - In Parkinson’s disease (PD) there is a selective degeneration of neuromelanin-containing neurons, especially substantia nigra dopaminergic neurons. In humans, neuromelanin accumulates with age, the latter being the main risk factor for PD. The contribution of neuromelanin to PD pathogenesis remains unknown because, unlike humans, common laboratory animals lack neuromelanin. Synthesis of peripheral melanins is mediated by tyrosinase, an enzyme also present at low levels in the brain. Here we report that overexpression of human tyrosinase in rat substantia nigra results in age-dependent production of human-like neuromelanin within nigral dopaminergic neurons, up to levels reached in elderly humans. In these animals, intracellular neuromelanin accumulation above a specific threshold is associated to an age-dependent PD phenotype, including hypokinesia, Lewy body-like formation and nigrostriatal neurodegeneration. Enhancing lysosomal proteostasis reduces intracellular neuromelanin and prevents neurodegeneration in tyrosinase-overexpressing animals. Our results suggest that intracellular neuromelanin levels may set the threshold for the initiation of PD.
AB - In Parkinson’s disease (PD) there is a selective degeneration of neuromelanin-containing neurons, especially substantia nigra dopaminergic neurons. In humans, neuromelanin accumulates with age, the latter being the main risk factor for PD. The contribution of neuromelanin to PD pathogenesis remains unknown because, unlike humans, common laboratory animals lack neuromelanin. Synthesis of peripheral melanins is mediated by tyrosinase, an enzyme also present at low levels in the brain. Here we report that overexpression of human tyrosinase in rat substantia nigra results in age-dependent production of human-like neuromelanin within nigral dopaminergic neurons, up to levels reached in elderly humans. In these animals, intracellular neuromelanin accumulation above a specific threshold is associated to an age-dependent PD phenotype, including hypokinesia, Lewy body-like formation and nigrostriatal neurodegeneration. Enhancing lysosomal proteostasis reduces intracellular neuromelanin and prevents neurodegeneration in tyrosinase-overexpressing animals. Our results suggest that intracellular neuromelanin levels may set the threshold for the initiation of PD.
UR - http://www.scopus.com/inward/record.url?scp=85062586891&partnerID=8YFLogxK
UR - http://www.scopus.com/inward/citedby.url?scp=85062586891&partnerID=8YFLogxK
U2 - 10.1038/s41467-019-08858-y
DO - 10.1038/s41467-019-08858-y
M3 - Article
C2 - 30846695
AN - SCOPUS:85062586891
VL - 10
JO - Nature Communications
JF - Nature Communications
SN - 2041-1723
IS - 1
M1 - 973
ER -