Fabio A. Zucca 1 , Renzo Vanna 1 , 2 , Francesca A. Cupaioli 1 , Chiara Bellei 1 , Antonella De Palma 1 , Dario Di Silvestre 1 , Pierluigi Mauri 1 , Sara Grassi 3 , Alessandro Prinetti 3 , Luigi Casella 4 , David Sulzer 5 , 6 , 7 , Luigi Zecca , 1 , 5
5 June 2018
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.
Subcellular compartments in the brain that contain a dark brown pigment, known as neuromelanin, function like a warehouse for a broad array of molecules not degraded by other cellular cleanup systems. Luigi Zecca from the National Research Council of Italy and colleagues characterized all of the proteins and lipid molecules found inside neuromelanin-containing organelles of the substantia nigra, a region of the human brain that is lost in Parkinson’s disease. They identified many proteins involved in the breakdown of molecules — a sign that this organelle is a degradative organelle known as an autolysosome. Interestingly, the number of these proteins was lower than in a typical lysosome, suggestive of impaired degradative ability. The authors conclude that these neuromelanin-containing organelles accumulate pigment, lipids, proteins, and other compounds over the lifetime of a neuron, possibly leading to cellular dysfunction and disease.