Objective: Because neuromelanin derives from the oxidation of free cytosolic dopamine, we hypothesized that enhancing dopamine vesicular encapsulation with vesicular monoamine transporter 2 (VMAT2) will decrease cytosolic dopamine that can convert to neuromelanin. This approach should slow down the intracellular buildup of neuromelanin that occurs with age and thus prevent, delay or attenuate PD pathology.

Background: In Parkinson’s disease (PD), there is a preferential degeneration of neurons that contain the pigment neuromelanin, especially dopaminergic neurons of the substantia nigra (SN), the loss of which leads to classical motor PD symptoms. We recently developed the first rodent model of human-like neuromelanin (NM) production based on the viral vector-mediated nigral expression of melanin-producing enzyme tyrosinase (AAV-hTyr). This has revealed that neuromelanin can trigger PD pathology when accumulated above a specific pathogenic threshold (1).

Method: Adult male Sprague-Dawley rats received single unilateral stereotaxic co-injections of AAV-hTyr and AAV-VMAT2 immediately above the SN. Control animals received equivalent amounts of either AAV-hTyr or AAV-VMAT2, separately. At selected times post-injection animals were assessed for motor asymmetry and their brains processed for histological and UPLC analyses.

Results: VMAT2 overexpression in hTyr-expressing rats reduced intracellular neuromelanin to levels below its pathogenic threshold by lowering the production of dopamine-oxidized neuromelanin precursors. In this regard, animals with VMAT2 overexpression exhibited lowered levels of oxidized dopamine and significant reductions in intracellular NM levels. Remarkably, reduction of intracellular neuromelanin levels was associated with an attenuation of PD-like motor deficits and nigrostriatal denervation in these animals. VMAT2 overexpression also restored early dopaminergic deficits that precede cell death and reduced the presence of NM-derived cellular debris and neuronophagic events.

Conclusion: The results presented herein demonstrate the feasibility and therapeutic potential of modulating intracellular neuromelanin levels in vivo by VMAT2 overexpression. 

Part of this abstract has been presented in Brain Conference 2021 (4-5 March) and AD/PD 2021 (9-14 March).

References: Carballo-Carbajal I, Laguna A, et al. Nature Communications (2019).

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MDS Abstracts - https://www.mdsabstracts.org/abstract/vmat2-overexpression-reduces-intracellular-neuromelanin-levels-and-attenuates-parkinson-like-pathology-in-neuromelanin-producing-parkinsonian-rats/