In vivoreduction of age-dependent neuromelanin accumulation mitigates features of Parkinson’s disease

Abstract

Humans accumulate with age the dark-brown pigment neuromelanin inside specific neuronal groups. Neurons with the highest neuromelanin levels are particularly susceptible to degeneration in Parkinson’s disease, especially dopaminergic neurons of the substantia nigra, the loss of which leads to characteristic motor Parkinson’s disease symptoms. In contrast to humans, neuromelanin does not appear spontaneously in most animals, including rodents, and Parkinson’s disease is an exclusively human condition. Using humanized neuromelanin-producing rodents, we recently found that neuromelanin can trigger Parkinson’s disease pathology when accumulated above a specific pathogenic threshold. Here, by taking advantage of this newly developed animal model, we assessed whether the intracellular build-up of neuromelanin that occurs with age can be slowed down in vivo to prevent or attenuate Parkinson’s disease. Because neuromelanin derives from the oxidation of free cytosolic dopamine, we enhanced dopamine vesicular encapsulation in the substantia nigra of neuromelanin-producing rats by viral vector-mediated overexpression of vesicular monoamine transporter 2 (VMAT2). This strategy reduced the formation of potentially toxic oxidized dopamine species that can convert into neuromelanin and maintained intracellular neuromelanin levels below their pathogenic threshold. Decreased neuromelanin production was associated with an attenuation of Lewy body-like inclusion formation and a long-term preservation of dopamine homeostasis, nigrostriatal neuronal integrity and motor function in these animals. Our results demonstrate the feasibility and therapeutic potential of modulating age-dependent intracellular neuromelanin production in vivo, thereby opening an unexplored path for the treatment of Parkinson’s disease and, in a broader sense, brain ageing.

Modelling human neuronal catecholaminergic pigmentation in rodents recapitulates age-related multisystem neurodegenerative deficits

“…However, a putative protective effect of NM has never been formally demonstrated, probably because of the lack of proper experimental models, and thus remains speculative to this day. In any case, even if we consider NM synthesis to be an initially beneficial process, this is compatible with a deleterious effect of its long-term age-dependent accumulation, by ultimately interfering with normal cell function and proteostasis in addition to an excess production of potentially toxic oxidized catechol intermediates, as we observed in NM-producing rodents (Carballo-Carbajal et al, 2019;Gonzalez-Sepulveda et al, 2023;Vila et al, 2019). Supporting this concept, reduction of intracellular NM accumulation in AAV-TYR-injected rats, either by boosting NM cytosolic clearance with autophagy activator TFEB or by delaying age-dependent NM production through VMAT2mediated enhancement of dopamine vesicular encapsulation, resulted in a major attenuation of their neurodegenerative phenotype, both at the behavioral and neuropathological level (Carballo-Carbajal et al, 2019;Gonzalez-Sepulveda et al, 2023).…”

“…TH, dopamine transporter [DAT] and vesicular monoamine transporter 2 [VMAT2]), as measured by Western blot in dissected tissue and/or by optical densitometry in immunostained histological sections (Figure S4C-D). While total dopamine (DA) levels were not changed in tgNM, as analyzed by ultra-performance liquid chromatography (UPLC) in striatal and SN-VTA tissue homogenates (Figure S5A), these animals exhibited alterations in DA metabolic pathways, including decreased DA synthesis and increased catechol oxidation, the latter producing DA oxidized species acting as NM precursors (Gonzalez-Sepulveda et al, 2023) (Figure S5B-C). In addition, striatal DA release, as assessed by in vivo microdialysis, was impaired in adult tgNM mice (Figure S5D), an age concurring with the appearance of behavioral alterations in these animals.…”

Neuromelanin accumulation drives endogenous synucleinopathy in non-human primates

“…Bearing in mind that NMel accumulation seems to be responsible for α-Syn pathology, it is perhaps worth considering alternative approaches intended to reduce intracellular NMel levels in an attempt to get rid of the subsequent synucleinopathy. Supporting this concept, reduction of intracellular NMel levels in vivo, either by boosting NMel cytosolic clearance with the autophagy activator TFEB 34 or by reducing NMel production with VMAT2-mediated enhancement of dopamine vesicular encapsulation 80 , resulted in a major attenuation of the PD phenotype, both at the behavioral and neuropathological levels, in AAV-hTyr-injected NMel-producing rats. Therefore, strategies decreasing age-dependent NMel building up may provide unprecedented therapeutic opportunities to either prevent, halt or delay neuronal dysfunction and degeneration linked to PD and, in a broader sense, brain aging.…”

Role of dopamine in the pathophysiology of Parkinson’s disease

“…Another study suggests that NM may be involved in α-syn-associated DA neuronal damage [ 29 ]. In NM-producing rats that show PD pathology when NM accumulates above a specific pathogenic threshold, the time-dependent accumulation of NM and degeneration of dopaminergic neurons under overexpression of tyrosinase, were significantly alleviated by viral vector-mediated overexpression of VMAT2 [ 30 ]. Furthermore, the reduced NM generation was associated with decreased formation of Lewy body-like inclusions and improved survival of dopaminergic neurons and motor functions in rats [ 30 ].…”

“…In NM-producing rats that show PD pathology when NM accumulates above a specific pathogenic threshold, the time-dependent accumulation of NM and degeneration of dopaminergic neurons under overexpression of tyrosinase, were significantly alleviated by viral vector-mediated overexpression of VMAT2 [ 30 ]. Furthermore, the reduced NM generation was associated with decreased formation of Lewy body-like inclusions and improved survival of dopaminergic neurons and motor functions in rats [ 30 ]. These findings highlight the potential pathological roles of NM accumulation in PD, suggesting therapeutic potentials of inhibiting time-dependent NM accumulation for PD.…”