Structural changes, including the abnormal distribution of lysosomes, were detected in neurons of a mouse model of Gaucher disease (GD) and identified as early signs preceding disease symptoms, a study suggests.
The study “Altered lysosome distribution is an early neuropathological event in neurological forms of Gaucher disease” was published in the FEBS Letters journal.
GD is divided into three clinical subtypes according to the age of disease onset and whether there is involvement of the central nervous system. In the neurological forms of the disease (nGD), types 2 and 3, the most characteristic feature is the “accumulation of lipid-laden macrophages as well as neuronal loss and neuroinflammation,” according to the study’s authors. Macrophages are a type of cell of the immune system; lipid-laden macrophages are the these cells that are full of undigested lipid, giving them a foamy appearance.
In the study, authors investigated which signaling pathways may become activated before neuron loss and microglia activation is noticeable in GD. Microglia are a type of immune cell (macrophage) found in the brain and spinal cord.
To this end, they analyzed brain tissue samples from a commonly used mouse model of GD. They observed that the distribution of a protein located in lysosomes, called lysosomal integral membrane protein 2 (Limp2), was altered in GD mice. Lysosomes are membrane-enclosed organelles inside our cells and where glucosylceramide (GlcCer) accumulates due to the defective activity of the enzyme glucocerebrosidase, the process at fault in GD. These results support lysosome mislocalization (displacement) in nGD neurons.
Authors investigated the mechanisms potentially underlying lysosome mislocalization in nGD and found that a defective functioning of a neuron’s cytoskeleton (the net of protein filaments and motor proteins that confer stability and help movement within the cell) may precede and potentially contribute to lysosomal mislocalization.
“These changes occur at an early stage in animal models of Gaucher disease, prior to development of overt symptoms and considerably earlier than neuronal loss. Altered lysosomal localization and cytoskeleton disruption precede the neuroinflammatory pathways, axonal dystrophy and neuronal loss previously characterized in neuronal forms of Gaucher disease,” the authors wrote.
Overall, mislocalized lysosomes and abnormalities to neurons’ cytoskeleton are an early event in nGD, which precedes disease symptoms, a phenomenon that may occur in other neurological diseases.