Lysosomal storage of heparan sulfate causes mitochondrial defects, altered autophagy, and neuronal death in the mouse model of mucopolysaccharidosis III type C

Niemann-Pick disease type C (NPC) disease is a neurodegenerative lysosomal storage disease caused by mutations in the NPC1 or NPC2 genes. Liver disease is also a common feature of NPC that can present as cholestatic jaundice in the neonatal period. Liver enzymes can remain elevated above the normal range in some patients as they age. We recently reported suppression of the P450 detoxification system in a mouse model of NPC disease and in post-mortem liver from NPC patients. As bile acids regulate the P450 system, we tested bile acid treatment using ursodeoxycholic acid (UDCA; 3α, 7β-dihydroxy-5β-cholanic acid), a hydrophilic bile acid, which is used to treat several cholestatic disorders. In this study, we compared UDCA treatment with the bile acid cholic acid (CA), and found unexpected hepatotoxicity in response to CA in Npc1 mice, but not to UDCA, suggesting that only UDCA should be used as an adjunctive therapy in NPC patients.

Download Full-text

Differential response of the liver to bile acid treatment in a mouse model of Niemann-Pick disease type C

Wellcome Open Research ◽

10.12688/wellcomeopenres.12431.2 ◽

2018 ◽

Vol 2 ◽

pp. 76

Author(s):

Elena-Raluca Nicoli ◽

Mylene Huebecker ◽

David Smith ◽

Lauren Morris ◽

Frances M. Platt

Keyword(s):

Bile Acid ◽

Mouse Model ◽

Disease Type ◽

Lysosomal Storage ◽

Niemann Pick Disease ◽

Type C ◽

Niemann Pick ◽

Npc Mouse ◽

Cholanic Acid ◽

Pick Disease

Niemann-Pick disease type C (NPC) disease is a neurodegenerative lysosomal storage disease caused by mutations in the NPC1 or NPC2 genes. Liver disease is also a common feature of NPC that can present as cholestatic jaundice in the neonatal period. Liver enzymes can remain elevated above the normal range in some patients as they age. We recently reported suppression of the P450 detoxification system in a mouse model of NPC disease and also in post-mortem liver from NPC patients. We demonstrated the ability of the hydrophobic bile acid ursodeoxycholic acid (UDCA) (3α, 7β-dihydroxy-5β-cholanic acid) to correct the P450 system suppression. UDCA is used to treat several cholestatic disorders and was tested in NPC due to the P450 system being regulated by bile acids. Here, we compare the effect of UDCA and cholic acid (CA), another bile acid, in the NPC mouse model. We observed unexpected hepatotoxicity in response to CA treatment of NPC mice. No such hepatotoxicity was associated with UDCA treatment. These results suggest that CA treatment is contraindicated in NPC patients, whilst supporting the use of UDCA as an adjunctive therapy in NPC patients.

Download Full-text

p35 Deficiency Accelerates HMGB-1-mediated Neuronal Death in the Early Stages of an Alzheimer’s disease Mouse Model

Current Alzheimer Research ◽

10.2174/15672050113109990135 ◽

2013 ◽

Vol 10 (8) ◽

pp. 829-843 ◽

Cited By ~ 12

Author(s):

Ahram Jang ◽

Hyunjeong Liew ◽

Yun-Mi Kim ◽

Heesoon Choi ◽

Saeromi Kim ◽

...

Keyword(s):

Alzheimer’S Disease ◽

Alzheimer's Disease ◽

Mouse Model ◽

Neuronal Death ◽

Early Stages

Download Full-text

Altered heparan sulfate metabolism during development triggers dopamine-dependent autistic-behaviours in models of lysosomal storage disorders

Nature Communications ◽

10.1038/s41467-021-23903-5 ◽

2021 ◽

Vol 12 (1) ◽

Author(s):

Maria De Risi ◽

Michele Tufano ◽

Filomena Grazia Alvino ◽

Maria Grazia Ferraro ◽

Giulia Torromino ◽

...

Keyword(s):

Heparan Sulfate ◽

Sch 23390 ◽

Lysosomal Storage Disorders ◽

Dopamine Neurons ◽

Therapeutic Effects ◽

Lysosomal Storage ◽

Cellular Models ◽

Mps Ii ◽

Mps Iiia ◽

Storage Disorders

AbstractLysosomal storage disorders characterized by altered metabolism of heparan sulfate, including Mucopolysaccharidosis (MPS) III and MPS-II, exhibit lysosomal dysfunctions leading to neurodegeneration and dementia in children. In lysosomal storage disorders, dementia is preceded by severe and therapy-resistant autistic-like symptoms of unknown cause. Using mouse and cellular models of MPS-IIIA, we discovered that autistic-like behaviours are due to increased proliferation of mesencephalic dopamine neurons originating during embryogenesis, which is not due to lysosomal dysfunction, but to altered HS function. Hyperdopaminergia and autistic-like behaviours are corrected by the dopamine D1-like receptor antagonist SCH-23390, providing a potential alternative strategy to the D2-like antagonist haloperidol that has only minimal therapeutic effects in MPS-IIIA. These findings identify embryonic dopaminergic neurodevelopmental defects due to altered function of HS leading to autistic-like behaviours in MPS-II and MPS-IIIA and support evidence showing that altered HS-related gene function is causative of autism.

Download Full-text

Beneficial Effects of Acetyl-DL-Leucine (ADLL) in a Mouse Model of Sandhoff Disease

Journal of Clinical Medicine ◽

10.3390/jcm9041050 ◽

2020 ◽

Vol 9 (4) ◽

pp. 1050 ◽

Cited By ~ 3

Author(s):

Ecem Kaya ◽

David A. Smith ◽

Claire Smith ◽

Barry Boland ◽

Michael Strupp ◽

...

Keyword(s):

Mouse Model ◽

Sandhoff Disease ◽

Lysosomal Storage ◽

Gm2 Ganglioside ◽

Beneficial Effects ◽

New Therapeutic Approaches ◽

Late Endosomes ◽

Altered Glucose ◽

Cerebellar Ataxias ◽

Niemann Pick

Sandhoff disease is a rare neurodegenerative lysosomal storage disease associated with the storage of GM2 ganglioside in late endosomes/lysosomes. Here, we explored the efficacy of acetyl-DL-leucine (ADLL), which has been shown to improve ataxia in observational studies in patients with Niemann–Pick Type C1 and other cerebellar ataxias. We treated a mouse model of Sandhoff disease (Hexb-/-) (0.1 g/kg/day) from 3 weeks of age with this orally available drug. ADLL produced a modest but significant increase in life span, accompanied by improved motor function and reduced glycosphingolipid (GSL) storage in the forebrain and cerebellum, in particular GA2. ADLL was also found to normalize altered glucose and glutamate metabolism, as well as increasing autophagy and the reactive oxygen species (ROS) scavenger, superoxide dismutase (SOD1). Our findings provide new insights into metabolic abnormalities in Sandhoff disease, which could be targeted with new therapeutic approaches, including ADLL.

Download Full-text