title: Involvement of the endosomal-lysosomal system correlates with regional pathology in Creutzfeldt-Jakob disease.
abstract: The endosomal-lysosomal system (ELS) has been suggested to play a role in the pathogenesis of prion diseases. The purpose of this study was to examine how experimental observations can be translated to human neuropathology and whether alterations of the ELS relate to neuropathologic changes. Combined with stereologic techniques, we examined components of the ELS in human sporadic Creutzfeldt-Jakob disease brains. We immunostained for the early endosomal marker Rab5 and lysosomal enzymes cathepsin D and B. We determined neuron-specific changes in their expression and correlated these with the severity of neuropathologic changes. In regions with mild pathology and scant abnormal prion protein (PrP) deposition, neurons showed an increased volume of Rab5-immunopositive early endosomes. In contrast, neurons in regions with prominent pathology had an increased volume of cathepsin D- or B-immunoreactive lysosomes. The intraneuronal distribution of cathepsin D and B diverges between Purkinje cells and frontal cortical neurons in sporadic Creutzfeldt-Jakob disease brains. We demonstrated focal intra- and perineuronal colocalization of cathepsin D and PrP. Our results indicate that effects in the ELS correlate with regional pathology. Overloading of this system might impair the function of lysosomal enzymes and thus may mimic some features of lysosomal storage disorders.
authors.affiliation: Institute of Neurology, Medical University of Vienna, and Austrian Reference Center for Human Prion Diseases, Vienna, Austria.
authors.forename: Gábor G
authors.initials: GG
authors.lastname: Kovács
authors.forename: Ellen
authors.initials: E
authors.lastname: Gelpi
authors.forename: Thomas
authors.initials: T
authors.lastname: Ströbel
authors.forename: Gerda
authors.initials: G
authors.lastname: Ricken
authors.forename: Jens R
authors.initials: JR
authors.lastname: Nyengaard
authors.forename: Hans
authors.initials: H
authors.lastname: Bernheimer
authors.forename: Herbert
authors.initials: H
authors.lastname: Budka
mesh_terms: D000368:Aged; D000369:Aged, 80 and over; D001921:Brain / Q000378:metabolism / Q000473:pathology*; D002403:Cathepsins / Q000378:metabolism; D007562:Creutzfeldt-Jakob Syndrome / Q000378:metabolism / Q000473:pathology*; D011992:Endosomes / Q000473:pathology*; D005260:Female; D005786:Gene Expression Regulation / Q000502:physiology; D006801:Humans; D007150:Immunohistochemistry; D008247:Lysosomes / Q000473:pathology*; D008297:Male; D008875:Middle Aged; D009474:Neurons / Q000378:metabolism / Q000473:pathology*; D011180:Postmortem Changes; D011328:Prions / Q000378:metabolism; D018709:Statistics, Nonparametric; D020696:rab5 GTP-Binding Proteins / Q000378:metabolism
chemical_list: D011328:Prions; D002403:Cathepsins; D020696:rab5 GTP-Binding Proteins