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Dopamine (DA) is one of the main neurotransmitters found in the central nervous system and has a vital role in the function of dopaminergic (DArgic) neurons. A progressive loss of this specific subset of cells is one of the hallmarks of age-related neurodegenerative disorders such as Parkinson's disease (PD). Symptomatic therapy for PD has been centered in the precursor l-DOPA administration, an amino acid precursor of DA that crosses the blood-brain barrier (BBB) while DA does not, although this approach presents medium- to long-term side effects. To overcome this limitation, DA-nanoencapsulation therapies are actively being searched as an alternative for DA replacement. However, overcoming the low yield of encapsulation and/or poor biodistribution/bioavailability of DA is still a current challenge. Herein, we report the synthesis of a family of neuromelanin bioinspired polymeric nanoparticles. Our system is based on the encapsulation of DA within nanoparticles through its reversible coordination complexation to iron metal nodes polymerized with a bis-imidazol ligand. Our methodology, in addition to being simple and inexpensive, results in DA loading efficiencies of up to 60%. In vitro, DA nanoscale coordination polymers (DA-NCPs) exhibited lower toxicity, degradation kinetics, and enhanced uptake by BE(2)-M17 DArgic cells compared to free DA. Direct infusion of the particles in the ventricle of rats in vivo showed a rapid distribution within the brain of healthy rats, leading to an increase in striatal DA levels. More importantly, after 4 days of nasal administrations with DA-NCPs equivalent to 200 μg of the free drug per day, the number and duration of apomorphine-induced rotations was significantly lower from that in either vehicle or DA-treated rats performed for comparison purposes. Overall, this study demonstrates the advantages of using nanostructured DA for DA-replacement therapy., This work was supported by grants RTI2018-098027-B-C21 and RTI2018-098027-B-C22 from the Spanish Government funds and by the European Regional Development Fund (ERDF). The ICN2 is funded by the CERCA program/Generalitat de Catalunya. The ICN2 is supported by the Severo Ochoa Centres of Excellence program, funded by the Spanish Research Agency (AEI, grant no. SEV-2017-0706). M.V. received funding from “la Caixa” Foundation (ID 1178 100010434, under the agreement LCF/PR/HR17/52150003) 1179, Ministry of Economy and Competitiveness (MINECO, Spain) (SAF2016-77541-R) and The Michael J. Fox Foundation for Parkinson’s Research 1180 (Grant ID: 15291.01). A.P.C. received funding from the ATTRACT project funded by the EC under Grant Agreement 777222. The authors thank the support from COST Action CA17121.

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., 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).