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 fibrillizated proteins including α-synuclein, identifying Krabbe disease as a new α-synucleinopathy.

Aberrant Production of Tenascin-C in Globoid Cell Leukodystrophy Alters Psychosine-Induced Microglial Functions

“…Additionally, neuronal source would be consistent with the colocalization of TnC foci that also stained for Thioflavin-S in the twitcher mouse brain. These findings are also in agreement with our recent report on the development of intraneuronal inclusions containing α-synuclein in GLD (51). Further analysis of GLD pathology is needed to improve our understanding of the cellular source of TnC in GLD and to characterize the composition of extracellular plaques identified by TnC staining patterns in this disease.…”

“…At MS lesions, increased TnC may have a beneficial role to promote cell growth but it is also possible that prolonged TnC elevations may also prevent the migration of progenitor cells necessary for mediating repair (49, 50). TnC deposits in twitcher brain exhibited a unique pattern of plaque-like clustering in multiple brain regions and some TnC-positive clusters were positive for Thioflavin-S, an amyloid marker (51). Additionally, neuronal source would be consistent with the colocalization of TnC foci that also stained for Thioflavin-S in the twitcher mouse brain.…”

Coupling of the non-amyloid-component (NAC) domain and the KTK(E/Q)GV repeats stabilize the α-synuclein fibrils

“…The aggregation of αS is closely related to several neurodegenerative diseases including Parkinson’s disease (PD) [1, 3]. Recently it was found that αS was present in aggregates of the Krabbe disease and apparently prone to fibrillization in the presence of psychosine [4]. αS adopts different conformations under various environments.…”

Patient fibroblasts-derived induced neurons demonstrate autonomous neuronal defects in adult-onset Krabbe disease

“…Moreover, psychosine has also been found to alter the angiogenesis process in the murine model, and linked to neuronal inclusion of misfolded and aggregated α-synuclein in postmortem brains from both infantile and late onset KD patients [10, 11]. These studies all point to potential autonomous neuronal dysfunction independent of myelin defects in leukodystrophic pathology, which may in fact precede myelin loss.…”