Intracellular crowding by age-dependent neuromelanin accumulation disrupts neuronal proteostasis and triggers Parkinson disease pathology

Abstract

In Parkinson disease (PD), there is a preferential degeneration of neurons that contain the dark-brown cytoplasmic pigment neuromelanin, in particular dopaminergic neurons of the substantia nigra (SN), the loss of which leads to the typical motor symptoms of the disease and constitutes the cardinal pathological diagnostic criterion for PD. Neuromelanin is generally considered a byproduct of dopamine oxidative metabolism and, in humans, it is first detected in early childhood and accumulates progressively with age until occupying most of the neuronal cytoplasm, as neurons apparently lack the means to degrade or eliminate this pigment. Aging is the main risk factor for developing PD, but the molecular substrate underlying this link remains unknown. Despite the close and long-established association between neuromelanin and PD, the potential contribution of neuromelanin to PD pathogenesis has remained elusive because, in contrast to humans, common laboratory animal species, such as rodents, lack neuromelanin. To overcome this major limitation, we have recently generated the first experimental in vivo rodent model exhibiting age-dependent production and accumulation of human-like neuromelanin within PD-vulnerable dopaminergic nigral neurons, at levels up to those reached in elderly humans.

Keywords: Alpha-synuclein; Lewy bodies; Parkinson’s disease; autophagy; cellular trafficking; dopamine; neurodegeneration; neuromelanin.

Figure 1.

Proposed pathogenic effects of age-dependent intracellular neuromelanin accumulation in humans (top) and HsTYR-overexpressing rats (bottom). The continuous, age-dependent intracellular buildup of neuromelanin within undegraded autophagic compartments above a specific pathogenic threshold of accumulation (dotted red line) is associated with a general failure of cellular proteostasis concomitant with lysosomal/autophagy dysfunction, UPS impairment, Lewy body-type inclusion formation, reduced mitochondrial respiration, increased production of reactive oxygen species, impaired neurotransmission, nigrostriatal neurodegeneration and neuroinflammation, all of which are major pathological features of PD. Enhancement of lysosomal-mediated proteolysis with TFEB reduces intracellular neuromelanin to levels below the pathogenic threshold, attenuates PD-like inclusion formation, prevents nigrostriatal neurodegeneration and reverses motor impairment in HsTYR-overexpressing rodents. Part of TFEB’s effects are attributed to enhanced exocytosis of neuromelanin-filled lysosomes outside the cell, thus supporting the feasibility and therapeutic potential of modulating intracellular neuromelanin levels in vivo.