Abnormal vacuoles distinct from lysosomes in a mouse model of mucopolysaccharidosis type IIIB

International audienceProgressive accumulation of large intracellular vesicles is a hallmark of cell pathology in lysosomal storage diseases. Accumulating vesicles are commonly identified as crippled lysosomes engorged with incompletely digested materials resulting form the genetic defect. Our study of cortical neurons of the mouse model of mucopolysaccharidosis IIIB (Sanfilippo syndrome type B), a lysosomal storage disease with predominant neurological manifestations, showed efficient endocytosis, macro-autophagy and trafficking between endoplasmic reticulum and Golgi. Vesicles accumulating in these cells have a unique membrane phenotype associating the lysosomal marker LAMP1 with markers of the early secretory pathway, suggesting that they do not result from amplification of the pre-existing lysosomal compartment but rather arise from disease-related vesicular trafficking defects producing abnormal dead-end organelles related to but distinct from lysosomes. The generation and accumulation of abnormal vesicles unable to resolve could be a major cause of progressive intracellular storage in mucopolysaccharidosis IIIB neurons

Heparan sulphate saccharides modify focal adhesions: Implication in mucopolysaccharidosis neuropathophysiology.

International audienceMucopolysaccharidoses type III (MPSIII, Sanfilippo syndrome) are genetic diseases due to deficient heparan sulphate saccharide digestion by lysosomal exoglycanases. Progressive accumulation of undigested saccharides causes early onset behavioural and cognitive symptoms. The precise role of these saccharides in the pathophysiological cascade is still unclear. We showed that exposure of wild type neural cells to exogenous soluble heparan sulphate fragments of at least eight saccharides activated integrin-based focal adhesions, which attach cells to the extracellular matrix. Focal adhesions were constitutively activated in MPSIII type B astrocytes or neural stem cells unless undigested saccharides were cleared by exogenous supply of the missing exoglycanase. Defective cell polarisation and oriented migration in response to focal extracellular stimuli in affected cells suggest improper sensing of the environment. We consistently observed abnormal organisation of the rostral migratory stream in the brain of adult mice with MPSIII type B. These results suggest that cell polarisation and oriented migration defects participate to the neurological disorders associated with Sanfilippo syndrome

Storage Vesicles in Neurons Are Related to Golgi Complex Alterations in Mucopolysaccharidosis IIIB

The accumulation of intracellular storage vesicles is a hallmark of lysosomal storage diseases. Neither the identity nor origin of these implicated storage vesicles have yet been established. The vesicles are often considered as lysosomes, endosomes, and/or autophagosomes that are engorged with undigested materials. Our studies in the mouse model of mucopolysaccharidosis type IIIB, a lysosomal storage disease that induces neurodegeneration, showed that large storage vesicles in cortical neurons did not receive material from either the endocytic or autophagy pathway, which functioned normally. Storage vesicles expressed GM130, a Golgi matrix protein, which mediates vesicle tethering in both pre- and cis-Golgi compartments. However, other components of the tethering/fusion complex were not associated with GM130 on storage vesicles, likely accounting for both the resistance of the vesicles to brefeldin A and the alteration of Golgi ribbon architecture, which comprised distended cisterna connected to LAMP1-positive storage vesicles. We propose that alteration in the GM130-mediated control of vesicle trafficking in pre-Golgi and Golgi compartments affects Golgi biogenesis and gives rise to a dead-end storage compartment. Vesicle accumulation, Golgi disorganization, and alterations of other GM130 functions may account for neuron dysfunction and death

Visions for nature and nature’s contributions to people for the 21st century : Report from an IPBES visioning workshop held on 4-8 September 2017 in Auckland, New Zealand

Existing scenarios of biodiversity and ecosystem services (BES) have important limitations and gaps that constrain their usefulness for the Intergovernmental Platform on Biodiversity and Ecosystem Services (IPBES). Specifically, they fail to incorporate policy objectives related to nature conservation and social-ecological feedbacks, they do not address the linkages between biodiversity and ecosystem services, and they are typically relevant at only a particular spatial scale. In addition, nature and its benefits are treated as the consequence of human decisions, but are not at the centre of the analysis. To address these issues, the IPBES Scenarios and Models Expert Group initiated the development of a set of Multiscale Scenarios for Nature Futures based on positive visions for human relationships with nature.The first step of this process was a visioning workshop with stakeholders and experts on 4-8 September 2017 in Auckland, New Zealand. A total of 73 participants from inter-governmental organisations, national government organisations, non-governmental organisations, academia and the private sector, from 31 countries, and with a range of sectoral expertise on biodiversity topics, from urban development to agriculture to fisheries, worked together in a visioning exercise. This report documents the results from this visioning workshop to inform further stakeholder consultation and the development of the associated multiscale scenarios by modelers and experts. This creative visioning exercise was carried out in four steps based on a suite of participatory methods that were used to develop visions of alternative futures. First the participants identified important themes to develop the visions. Next, thematic groups identified the main trends for BES in each theme and a set of “Seeds” of emerging initiatives leading to positive futures for our relationship with nature. Implications of what would happen across a range of sectors were identified for each seed. Then a pathway analysis of how the current regime in each theme may be transformed into the future desirable regime was carriedout. Narratives were then built for the visions emerging from each group. Finally, commonalities of visions across the groups were identified, and the regional relevance of each vision for different parts of the world was assessed

Visions for nature and nature’s contributions to people for the 21st century : Report from an IPBES visioning workshop held on 4-8 September 2017 in Auckland, New Zealand

Existing scenarios of biodiversity and ecosystem services (BES) have important limitations and gaps that constrain their usefulness for the Intergovernmental Platform on Biodiversity and Ecosystem Services (IPBES). Specifically, they fail to incorporate policy objectives related to nature conservation and social-ecological feedbacks, they do not address the linkages between biodiversity and ecosystem services, and they are typically relevant at only a particular spatial scale. In addition, nature and its benefits are treated as the consequence of human decisions, but are not at the centre of the analysis. To address these issues, the IPBES Scenarios and Models Expert Group initiated the development of a set of Multiscale Scenarios for Nature Futures based on positive visions for human relationships with nature.The first step of this process was a visioning workshop with stakeholders and experts on 4-8 September 2017 in Auckland, New Zealand. A total of 73 participants from inter-governmental organisations, national government organisations, non-governmental organisations, academia and the private sector, from 31 countries, and with a range of sectoral expertise on biodiversity topics, from urban development to agriculture to fisheries, worked together in a visioning exercise. This report documents the results from this visioning workshop to inform further stakeholder consultation and the development of the associated multiscale scenarios by modelers and experts. This creative visioning exercise was carried out in four steps based on a suite of participatory methods that were used to develop visions of alternative futures. First the participants identified important themes to develop the visions. Next, thematic groups identified the main trends for BES in each theme and a set of “Seeds” of emerging initiatives leading to positive futures for our relationship with nature. Implications of what would happen across a range of sectors were identified for each seed. Then a pathway analysis of how the current regime in each theme may be transformed into the future desirable regime was carriedout. Narratives were then built for the visions emerging from each group. Finally, commonalities of visions across the groups were identified, and the regional relevance of each vision for different parts of the world was assessed