GBA1 inactivation in oligodendrocytes affects myelination and induces neurodegenerative hallmarks and lipid dyshomeostasis in mice

Abstract

Background Mutations in the β-glucocerebrosidase (GBA1) gene do cause the lysosomal storage Gaucher disease (GD) and are among the most frequent genetic risk factors for Parkinson’s disease (PD). So far, studies on both neuronopathic GD and PD primarily focused on neuronal manifestations, besides the evaluation of microglial and astrocyte implication. White matter alterations were described in the central nervous system of paediatric type 1 GD patients and were suggested to sustain or even play a role in the PD process, although the contribution of oligodendrocytes has been so far scarcely investigated. Methods We exploited a system to study the induction of central myelination in vitro, consisting of Oli-neu cells treated with dibutyryl-cAMP, in order to evaluate the expression levels and function of β-glucocerebrosidase during oligodendrocyte differentiation. Conduritol-B-epoxide, a β-glucocerebrosidase irreversible inhibitor was used to dissect the impact of β-glucocerebrosidase inactivation in the process of myelination, lysosomal degradation and α-synuclein accumulation in vitro. Moreover, to study the role of β-glucocerebrosidase in the white matter in vivo, we developed a novel mouse transgenic line in which β-glucocerebrosidase function is abolished in myelinating glia, by crossing the Cnp1-cre mouse line with a line bearing loxP sequences flanking Gba1 exons 9–11, encoding for β-glucocerebrosidase catalytic domain. Immunofluorescence, western blot and lipidomic analyses were performed in brain samples from wild-type and knockout animals in order to assess the impact of genetic inactivation of β-glucocerebrosidase on myelination and on the onset of early neurodegenerative hallmarks, together with differentiation analysis in primary oligodendrocyte cultures. Results Here we show that β-glucocerebrosidase inactivation in oligodendrocytes induces lysosomal dysfunction and inhibits myelination in vitro. Moreover, oligodendrocyte-specific β-glucocerebrosidase loss-of-function was sufficient to induce in vivo demyelination and early neurodegenerative hallmarks, including axonal degeneration, α-synuclein accumulation and astrogliosis, together with brain lipid dyshomeostasis and functional impairment. Conclusions Our study sheds light on the contribution of oligodendrocytes in GBA1-related diseases and supports the need for better characterizing oligodendrocytes as actors playing a role in neurodegenerative diseases, also pointing at them as potential novel targets to set a brake to disease progression.

Is There a Place for Lewy Bodies before and beyond Alpha-Synuclein Accumulation? Provocative Issues in Need of Solid Explanations

“…Based on the significance of mutated genes in causing inherited PD, the relevance of these interconnected compartments involved in cell clearance emerged in sporadic PD. These compartments include autophagosomes [36,38,[43][44][45][46][47], proteasome [34,48], endosomes [49,50], retromers [51,52], lysosomes [53][54][55][56][57], mitochondrial turnover [39,[58][59][60][61], and primary protein misfolding [62][63][64].…”

The mechanisms of white matter injury and immune system crosstalk in promoting the progression of Parkinson’s disease: a narrative review

“…Recent studies have underscored the importance of abnormalities in PD brain white matter structure and function, particularly changes in myelin and the role of oligodendrocytes ( Yang et al, 2023 ). α-Syn, primarily associated with neurons, can also accumulate in oligodendrocytes ( Gregorio et al, 2024 ). This not only affects the function of oligodendrocytes but also impacts myelin maintenance and neural signal transmission.…”

“…Specifically, neural fibers in the PD brain might suffer myelin damage due to oligodendrocyte dysfunction, leading to slowed neural signal transmission and affecting patients’ motor abilities and other neurological functions. As research into PD deepens, the role of oligodendrocytes and their associated myelin in the disease is increasingly recognized, yet studies on how oligodendrocytes promote PD pathological progression and the specific mechanisms and signaling pathways are scarce ( Mavroeidi et al, 2022 ; Wang et al, 2022 ; Gregorio et al, 2024 ). Future research might reveal more about these cells’ specific mechanisms in PD, offering new directions for PD treatment.…”

“…On the other hand, the state of oxidative stress present in PD patients exacerbates damage to microglia and oligodendrocytes, leading to lipid peroxidation of cell membranes, protein oxidation, and DNA damage, further promoting the aggregation of α-syn and neurodegenerative lesions. For instance, some studies have shown that oligodendrocyte defects can cause aggregation of α-synuclein, axonal defects, activation of microglia, and astrocyte proliferation, revealing their role in neurodegenerative diseases and the complex pathological processes they cause ( Festa et al, 2024 ; Gregorio et al, 2024 ).…”