N-butyldeoxynojirimycin delays motor deficits, cerebellar microgliosis, and Purkinje cell loss in a mouse model of mucolipidosis type IV

Boudewyn, Lauren C.; Sikora, Jakub; Kuchař, Ladislav; Ledvinová, Jana; Grishchuk, Yulia; Wang, Shirley L.; Dobrenis, Kostantin; Walkley, Steven U.

doi:10.1016/j.nbd.2017.06.003

Cited by 15 publications

(22 citation statements)

References 68 publications

Supporting

Mentioning

Contrasting

Order By: Relevance

“…Such treatment should be started at very early stages of the disease as we showed early accumulation of gangliosides in lysosomes, both in the Spg11 knockout mouse model and human SPG11 iPSC-derived neurons. However, it was not possible to test this hypothesis in the Spg11 −/− mouse model due to the controversial action of miglustat on brain glycosphingolipids ( Ashe et al., 2011 , Boudewyn et al., 2017 ).…”

Section: Discussionmentioning

confidence: 99%

Inhibition of Lysosome Membrane Recycling Causes Accumulation of Gangliosides that Contribute to Neurodegeneration

et al. 2018

Self Cite

View full text Add to dashboard Cite

SummaryLysosome membrane recycling occurs at the end of the autophagic pathway and requires proteins that are mostly encoded by genes mutated in neurodegenerative diseases. However, its implication in neuronal death is still unclear. Here, we show that spatacsin, which is required for lysosome recycling and whose loss of function leads to hereditary spastic paraplegia 11 (SPG11), promotes clearance of gangliosides from lysosomes in mouse and human SPG11 models. We demonstrate that spatacsin acts downstream of clathrin and recruits dynamin to allow lysosome membrane recycling and clearance of gangliosides from lysosomes. Gangliosides contributed to the accumulation of autophagy markers in lysosomes and to neuronal death. In contrast, decreasing ganglioside synthesis prevented neurodegeneration and improved motor phenotype in a SPG11 zebrafish model. Our work reveals how inhibition of lysosome membrane recycling leads to the deleterious accumulation of gangliosides, linking lysosome recycling to neurodegeneration.

show abstract

Section: Discussionmentioning

confidence: 99%

Inhibition of Lysosome Membrane Recycling Causes Accumulation of Gangliosides that Contribute to Neurodegeneration

et al. 2018

Self Cite

View full text Add to dashboard Cite

show abstract

“…Based on this observation, treatments reducing microglial activation in the first three diseases and reducing disease burden should be evaluated in MLIV. Work by Boudewyn et al [29] have shown that miglustat, a drug which decreases microgliosis in NPC1 mice, is effective in MLIV. Based on these observations, we could expect the inhibition of receptor-interacting protein kinase 1 or 3, which have been suggested to reduce the neuroinflammation in lysosomal storage diseases [57, 58] and could be considered for therapeutic intervention in MLIV.…”

Section: Discussionmentioning

confidence: 99%

“…This model is characterized by early gliosis that decreases with disease progression accompanied by a progressive loss of motor function in the later stages of the disease [17, 20, 28]. Although there are no current medical therapies for patients with MLIV, bone marrow transplantation and N-butyl-deoxynojirimycin (miglustat) have been shown to delay the pathologic progression in the mouse model of MLIV [28, 29].…”

Section: Introductionmentioning

confidence: 99%

Unique molecular signature in mucolipidosis type IV microglia

Cougnoux

Drummond

Fellmeth

et al. 2019

J Neuroinflammation

View full text Add to dashboard Cite

BackgroundLysosomal storage diseases (LSD) are a large family of inherited disorders characterized by abnormal endolysosomal accumulation of cellular material due to catabolic enzyme and transporter deficiencies. Depending on the affected metabolic pathway, LSD manifest with somatic or central nervous system (CNS) signs and symptoms. Neuroinflammation is a hallmark feature of LSD with CNS involvement such as mucolipidosis type IV, but not of others like Fabry disease.MethodsWe investigated the properties of microglia from LSD with and without major CNS involvement in 2-month-old mucolipidosis type IV (Mcoln1−/−) and Fabry disease (Glay/−) mice, respectively, by using a combination of flow cytometric, RNA sequencing, biochemical, in vitro and immunofluorescence analyses.ResultsWe characterized microglia activation and transcriptome from mucolipidosis type IV and Fabry disease mice to determine if impaired lysosomal function is sufficient to prime these brain-resident immune cells. Consistent with the neurological pathology observed in mucolipidosis type IV, Mcoln1−/− microglia demonstrated an activation profile with a mixed neuroprotective/neurotoxic expression pattern similar to the one we previously observed in Niemann-Pick disease, type C1, another LSD with significant CNS involvement. In contrast, the Fabry disease microglia transcriptome revealed minimal alterations, consistent with the relative lack of CNS symptoms in this disease. The changes observed in Mcoln1−/− microglia showed significant overlap with alterations previously reported for other common neuroinflammatory disorders including Alzheimer’s, Parkinson’s, and Huntington’s diseases. Indeed, our comparison of microglia transcriptomes from Alzheimer’s disease, amyotrophic lateral sclerosis, Niemann-Pick disease, type C1 and mucolipidosis type IV mouse models showed an enrichment in “disease-associated microglia” pattern among these diseases.ConclusionsThe similarities in microglial transcriptomes and features of neuroinflammation and microglial activation in rare monogenic disorders where the primary metabolic disturbance is known may provide novel insights into the immunopathogenesis of other more common neuroinflammatory disorders.Trial registrationClinicalTrials.gov, NCT01067742, registered on February 12, 2010

show abstract

“…Our findings are consistent with studies in mouse models of NPCD [95] as well as other LSDs [96,97] where miglustat was found to be disease-modifying despite increased levels of brain GlcCer, which is inconsistent with synthase inhibition. We think it is significant that recent reports point to a key role for lysosomal acidification in LSDs and neurodegenerative diseases more generally [13,98,99]. GBA2 and vATPase are therefore potential drug targets for NPCD and other diseases of lysosomal dysfunction.…”

Section: Accepted Manuscriptmentioning

confidence: 96%

Cytosolic glucosylceramide regulates endolysosomal function in Niemann-Pick type C disease

Wheeler

Haberkant

Bhardwaj

et al. 2019

Neurobiology of Disease

View full text Add to dashboard Cite

Niemann-Pick type C disease (NPCD) is a neurodegenerative disease associated with increases in cellular cholesterol and glycolipids and most commonly caused by defective NPC1, a late endosomal protein. Using ratiometric probes we find that NPCD cells show increased endolysosomal pH. In addition U18666A, an inhibitor of NPC1, was found to increase endolysosomal pH, and the number, size and heterogeneity of endolysosomal vesicles. NPCD fibroblasts and cells treated with U18666A also show disrupted targeting of fluorescent lipid BODIPY-LacCer to high pH vesicles. Inhibiting non-lysosomal glucocerebrosidase (GBA2) reversed increases in endolysosomal pH and restored disrupted BODIPY-LacCer trafficking in NPCD fibroblasts. GBA2 KO cells also show decreased endolysosomal pH. NPCD fibroblasts also show increased expression of a key subunit of the lysosomal proton pump vATPase on GBA2 inhibition. The results are consistent with a model where both endolysosomal pH and Golgi targeting of BODIPY-LacCer are dependent on adequate levels of cytosolic-facing GlcCer, which are reduced in NPC disease. Niemann-Pick type C disease (NPCD) is a devastating neurodegenerative condition most commonly due to mutations in NPC1 [1,2] a protein of late endosomes and lysosomes [3]. (Due to difficulties in precisely distinguishing these two sets of organelles the term endolysosome will be used here to include both.) Mutations in NPC1 are associated with impaired endocytic transport via decreased endolysosomal calcium release [4,5]. In turn, endocytosis and luminal calcium are dependent on correct endolysosomal acidification [4] and have been found to be controlled by glycolipids in neurons [6], melanocytes [7], plant vacuoles [8] and C. elegans [9]. It is increasingly apparent that aberrant lysosomal GlcCer in Gaucher disease is associated with elevated endolysosomal pH [10-13]. Glycolipids, vital for mammals [14], are also implicated in membrane trafficking [10,15]. Similarly in yeast the NPC1 homologue ncr1 regulates both vacuolar pH [16] and glycolipid transport [17]. An overview of sphingolipid metabolism highlighting the connection with endocytosis is offered in Fig. S1. Does NPC1 affect endolysosomal pH? Conflicting evidence has been found both in disease fibroblasts [5,16,18-20] and in cells treated with U18666A, a putative inhibitor of NPC1 [5,21-23]. If endocytic traffic is delayed then probes which permeate all acidic organelles will show increased pH values even though fully mature lysosomes still acidify correctly. We used such a general probe to

show abstract

N-butyldeoxynojirimycin delays motor deficits, cerebellar microgliosis, and Purkinje cell loss in a mouse model of mucolipidosis type IV

Cited by 15 publications

References 68 publications

Inhibition of Lysosome Membrane Recycling Causes Accumulation of Gangliosides that Contribute to Neurodegeneration

Inhibition of Lysosome Membrane Recycling Causes Accumulation of Gangliosides that Contribute to Neurodegeneration

Unique molecular signature in mucolipidosis type IV microglia

Cytosolic glucosylceramide regulates endolysosomal function in Niemann-Pick type C disease

Contact Info

Product

Resources

About