title: Neuronal inclusions of α-synuclein contribute to the pathogenesis of Krabbe disease.
abstract: Demyelination is a major contributor to the general decay of neural functions in children with Krabbe disease. However, recent reports have indicated a significant involvement of neurons and axons in the neuropathology of the disease. In this study, we have investigated the nature of cellular inclusions in the Krabbe brain. Brain samples from the twitcher mouse model for Krabbe disease and from patients affected with the infantile and late-onset forms of the disease were examined for the presence of neuronal inclusions. Our experiments demonstrated the presence of cytoplasmic aggregates of thioflavin-S-reactive material in both human and murine mutant brains. Most of these inclusions were associated with neurons. A few inclusions were detected to be associated with microglia and none were associated with astrocytes or oligodendrocytes. Thioflavin-S-reactive inclusions increased in abundance, paralleling the development of neurological symptoms, and distributed throughout the twitcher brain in areas of major involvement in cognition and motor functions. Electron microscopy confirmed the presence of aggregates of stereotypic β-sheet folded proteinaceous material. Immunochemical analyses identified the presence of aggregated forms of α-synuclein and ubiquitin, proteins involved in the formation of Lewy bodies in Parkinson's disease and other neurodegenerative conditions. In vitro assays demonstrated that psychosine, the neurotoxic sphingolipid accumulated in Krabbe disease, accelerated the fibrillization of α-synuclein. This study demonstrates the occurrence of neuronal deposits of fibrillized proteins including α-synuclein, identifying Krabbe disease as a new α-synucleinopathy.
authors.affiliation: Department of Anatomy and Cell Biology, College of Medicine, University of Illinois, University of Illinois Chicago, Chicago, IL, 60612, USA.
authors.forename: Benjamin R
authors.initials: BR
authors.lastname: Smith
authors.forename: Marta B
authors.initials: MB
authors.lastname: Santos
authors.forename: Michael S
authors.initials: MS
authors.lastname: Marshall
authors.forename: Ludovico
authors.initials: L
authors.lastname: Cantuti-Castelvetri
authors.forename: Aurora
authors.initials: A
authors.lastname: Lopez-Rosas
authors.forename: Guannan
authors.initials: G
authors.lastname: Li
authors.forename: Richard
authors.initials: R
authors.lastname: van Breemen
authors.forename: Kumiko I
authors.initials: KI
authors.lastname: Claycomb
authors.forename: Jose I
authors.initials: JI
authors.lastname: Gallea
authors.forename: Maria S
authors.initials: MS
authors.lastname: Celej
authors.forename: Stephen J
authors.initials: SJ
authors.lastname: Crocker
authors.forename: Maria I
authors.initials: MI
authors.lastname: Givogri
authors.forename: Ernesto R
authors.initials: ER
authors.lastname: Bongarzone
mesh_terms: D000818:Animals; D052160:Benzothiazoles; D001921:Brain / Q000378:metabolism* / Q000503:physiopathology / Q000648:ultrastructure; D016022:Case-Control Studies; D003071:Cognition; D004195:Disease Models, Animal; D005456:Fluorescent Dyes; D006801:Humans; D007965:Leukodystrophy, Globoid Cell / Q000235:genetics / Q000378:metabolism* / Q000473:pathology / Q000503:physiopathology / Q000523:psychology; D016631:Lewy Bodies / Q000378:metabolism* / Q000648:ultrastructure; D051379:Mice; D009043:Motor Activity; D009154:Mutation; D009474:Neurons / Q000378:metabolism* / Q000648:ultrastructure; D011609:Psychosine / Q000378:metabolism; D013844:Thiazoles; D051844:alpha-Synuclein / Q000235:genetics / Q000378:metabolism*
chemical_list: D052160:Benzothiazoles; D005456:Fluorescent Dyes; C497604:SNCA protein, human; C497605:Snca protein, mouse; D013844:Thiazoles; D051844:alpha-Synuclein; D011609:Psychosine; C009462:thioflavin T
keywords: Krabbe disease; Lewy bodies; axonal degeneration; dying-back pathology; myelin; psychosine; synucleinopathies; ubiquitin; α-synuclein