Neuromelanin Organelles, a Garbage Dump of Last Resort in Aging Brain Cells

Autophagy is a collection of several quality control processes in which broken cell components, damaged proteins, and metabolic waste are broken down and recycled. In the most familiar of these processes, the material to be recycled is wrapped in a membrane, an autophagosome, which then migrates to a lysosome, another membrane-bound organelle packed with enzymes capable of taking apart just about any molecule it is likely to encounter.

Unfortunately, this recycling process falters with age in a number of ways, the consequences particularly apparent in very long-lived cells such as the neurons of the central nervous system. Lysosomes become packed with the few classes of compound that they struggle to break down, growing inefficient and bloated. Autophagosomes lose the mechanisms required to transport their contents efficiently to their destination. Cells become overwhelmed with metabolic waste, and dysfunctional as a result.

This open access paper describes one of the outcomes of this decline, the accumulation of garbage dump organelles inside brain cells, probably lysosomes or autophagosomes or the fusion of both that have come to the point of outright failure of function. If autophagy can be restored in aged neurons, will these additional waste-packed organelles start to vanish? That would be one of the more direct ways to try to get a handle on cause and effect, and there are a few possible approaches to that end that might work well enough in the lab to obtain useful data. The ones I tend to favor are those of the LysoSENS program: find ways to break down the worst and most persistent metabolic waste, which should allow lysosomes to cope with the rest.

During aging, neuronal organelles filled with neuromelanin (a dark-brown pigment) and lipid bodies accumulate in the brain, particularly in the substantia nigra, a region targeted in Parkinson's disease. We have investigated protein and lipid systems involved in the formation of these organelles and in the synthesis of the neuromelanin of human substantia nigra. Membrane and matrix proteins characteristic of lysosomes were found in neuromelanin-containing organelles at a lower number than in typical lysosomes, indicating a reduced enzymatic activity and likely impaired capacity for lysosomal and autophagosomal fusion.

The presence of proteins involved in lipid transport may explain the accumulation of lipid bodies in the organelle and the lipid component in neuromelanin structure. The major lipids observed in lipid bodies of the organelle are dolichols with lower amounts of other lipids. Proteins of aggregation and degradation pathways were present, suggesting a role for accumulation by this organelle when the ubiquitin-proteasome system is inadequate. The presence of proteins associated with aging and storage diseases may reflect impaired autophagic degradation or impaired function of lysosomal enzymes.

The identification of typical autophagy proteins and double membranes demonstrates the organelle's autophagic nature and indicates that it has engulfed neuromelanin precursors from the cytosol. Based on these data, it appears that the neuromelanin-containing organelle has a very slow turnover during the life of a neuron and represents an intracellular compartment of final destination for numerous molecules not degraded by other systems.

Link: https://doi.org/10.1038/s41531-018-0050-8

Comments

Is there an easy and non-invasive method to measure the levels of neuromelanin and the state of autorisations on humans (without brain samples)?

Posted by: Cuberat at June 22nd, 2018 3:46 PM

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