Glucocerebrosidase is imported into mitochondria and preserves complex I integrity and energy metabolism

Mutations in GBA1, the gene encoding the lysosomal enzyme β-glucocerebrosidase (GCase), which cause Gaucher's disease, are the most frequent genetic risk factor for Parkinson's disease (PD). Here, we employ global proteomic and single-cell genomic approaches in stable cell lines as well as induced pluripotent stem cell (iPSC)-derived neurons and midbrain organoids to dissect the mechanisms underlying GCase-related neurodegeneration. We demonstrate that GCase can be imported from the cytosol into the mitochondria via recognition of internal mitochondrial targeting sequence-like signals. In mitochondria, GCase promotes the maintenance of mitochondrial complex I (CI) integrity and function. Furthermore, GCase interacts with the mitochondrial quality control proteins HSP60 and LONP1. Disease-associated mutations impair CI stability and function and enhance the interaction with the mitochondrial quality control machinery. These findings reveal a mitochondrial role of GCase and suggest that defective CI activity and energy metabolism may drive the pathogenesis of GCase-linked neurodegeneration

Glycolipids in Parkinson's disease: beyond neuronal function

Glycolipid balance is key to normal body function, and its alteration can lead to a variety of diseases involving multiple organs and tissues. Glycolipid disturbances are also involved in Parkinson's disease (PD) pathogenesis and aging. Increasing evidence suggests that glycolipids affect cellular functions beyond the brain, including the peripheral immune system, intestinal barrier, and immunity. Hence, the interplay between aging, genetic predisposition, and environmental exposures could initiate systemic and local glycolipid changes that lead to inflammatory reactions and neuronal dysfunction. In this review, we discuss recent advances in the link between glycolipid metabolism and immune function and how these metabolic changes can exacerbate immunological contributions to neurodegenerative diseases, with a focus on PD. Further understanding of the cellular and molecular mechanisms that control glycolipid pathways and their impact on both peripheral tissues and the brain will help unravel how glycolipids shape immune and nervous system communication and the development of novel drugs to prevent PD and promote healthy aging

Structural determinants of CO2-sensitivity in the β connexin family suggested by evolutionary analysis

none8siA subclade of connexins comprising Cx26, Cx30, and Cx32 are directly sensitive to CO2. CO2 binds to a carbamylation motif present in these connexins and causes their hemichannels to open. Cx26 may contribute to CO2-dependent regulation of breathing in mammals. Here, we show that the carbamylation motif occurs in a wide range of non-mammalian vertebrates and was likely present in the ancestor of all gnathostomes. While the carbamylation motif is essential for connexin CO2-sensitivity, it is not sufficient. In Cx26 of amphibia and lungfish, an extended C-terminal tail prevents CO2-evoked hemichannel opening despite the presence of the motif. Although Cx32 has a long C-terminal tail, Cx32 hemichannels open to CO2 because the tail is conformationally restricted by the presence of proline residues. The loss of the Cterminal tail of Cx26 in amniotes was an evolutionary innovation that created a connexin hemichannel with CO2-sensing properties suitable for the regulation of breathing.noneDospinescu V.-M.; Nijjar S.; Spanos F.; Cook J.; de Wolf E.; Biscotti M.A.; Gerdol M.; Dale N.Dospinescu, V. -M.; Nijjar, S.; Spanos, F.; Cook, J.; de Wolf, E.; Biscotti, M. A.; Gerdol, M.; Dale, N

Glucocerebrosidase is imported into mitochondria and preserves complex I integrity and energy metabolism

GBA1 mutations cause Gaucher’s disease and are the strongest risk factor for Parkinson’s disease. Using stable cell lines and patient iPSCs, the authors show mitochondrial localization of GBA1, which may affect neurodegenerative disease risk