Increased neuronal Rab5 immunoreactive endosomes do not colocalize with TDP-43 in motor neuron disease.
Sporadic motor neuron disease (MND) is characterized by progressive degeneration of motor neurons and intraneuronal cytoplasmic translocation and deposition of the nuclear protein TDP-43. There is a paucity of data on the subcellular mechanisms of the nuclear-cytoplasmic trafficking of TDP-43, particularly about the precise role of the endosomal-lysosomal system (ELS). In the present study, using a neuron-specific morphometric approach, we examined the expression of the early endosomal marker Rab5 and lysosomal cathepsins B, D, F, and L as well as PAS-stained structures in the anterior horn cells in 11 individuals affected by sporadic MND and 5 age-matched controls. This was compared with the expression of ubiquitin, p62 and TDP-43 and its phosphorylated form. The principal finding was the increased expression of the endosomal marker Rab5 and lysosomal cathepsin D, and of PAS-positive structures in motor neurons of MND cases. Furthermore, the area-portion of Rab5 immunoreactivity correlated well with the intracellular accumulation of ubiquitin, p62 and (phosphorylated) TDP-43. However, double immunolabelling and immunogold electron microscopy excluded colocalization of phosphorylated TDP-43 with the ELS. These data contrast with observations on neuronal cytopathology in Alzheimer's or prion diseases where the disease-specific proteins are processed within endosomes, and suggest a distinct role of the ELS in MND.
Matej
Radoslav
R
Institute of Neurology, Medical University of Vienna, Vienna, Austria.
Botond
Gergö
G
László
Lajos
L
Kopitar-Jerala
Natasa
N
Rusina
Robert
R
Budka
Herbert
H
Kovacs
Gabor G
GG
D021581:Active Transport, Cell Nucleus / Q000235:genetics; D000368:Aged; D004268:DNA-Binding Proteins / Q000235:genetics / Q000378:metabolism* / Q000648:ultrastructure; D011992:Endosomes / Q000378:metabolism* / Q000473:pathology* / Q000648:ultrastructure; D005260:Female; D006801:Humans; D007424:Intracellular Fluid / Q000737:chemistry / Q000378:metabolism; D008247:Lysosomes / Q000378:metabolism / Q000473:pathology / Q000648:ultrastructure; D008297:Male; D008875:Middle Aged; D016472:Motor Neuron Disease / Q000378:metabolism* / Q000473:pathology*; D010766:Phosphorylation / Q000235:genetics; D021381:Protein Transport / Q000235:genetics; D020696:rab5 GTP-Binding Proteins / Q000096:biosynthesis* / Q000235:genetics / Q000648:ultrastructure
D004268:DNA-Binding Proteins; D020696:rab5 GTP-Binding Proteins