L-leucine and SPNS1 coordinately ameliorate dysfunction of autophagy in mouse and human Niemann-Pick type C disease

Yanagisawa, Hiroko; Ishii, Takemochi; Endo, Kentaro; Kawakami, Emiko; Nagao, Keiko; Miyashita, Toshiyuki; Akiyama, Keiko; Watabe, Kazuhiko; Komatsu, Masaaki; Yamamoto, Daisuke; Eto, Yoshikatsu

doi:10.1038/s41598-017-15305-9

Cited by 24 publications

(23 citation statements)

References 40 publications

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“…The mechanistic target of rapamycin (mTOR) is a master regulator of anabolic metabolism and it suppresses catabolic pathways such as autophagy [23]. Leucine increases phosphorylation of mTOR and subsequent activation, as recently reported in NPC fibroblasts [24]. Phosphorylated mTOR (p-mTOR) levels were significantly decreased in Hexb -/cerebellum (48.1%, p = 0.0456) compared to Hexb +/+ cerebellum (Figure 2a,b).…”

Section: Adll Increases Autophagy In Hexb -/-Mice Cerebellumsupporting

confidence: 70%

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

Kaya

Smith

et al. 2020

JCM

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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.

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Section: Adll Increases Autophagy In Hexb -/-Mice Cerebellumsupporting

confidence: 70%

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

Kaya

Smith

et al. 2020

JCM

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“…Therefore, we investigated aspects of cell biology and metabolism known to be sensitive to leucine. Leucine has been shown to activate mTOR and reduce LC3-II and p62 in NPC1 cells (Yanagisawa et al, 2017). However, in this study, ADLL, ALL and ADL did not significantly affect either mTOR or autophagy in Npc1 -/mouse cerebellum.…”

Section: Discussioncontrasting

confidence: 71%

“…As L-Leucine is a potent activator of the mammalian target of rapamycin (mTOR) (Kimball et al, 1999), which negatively regulates autophagy (Klionsky and Emr, 2000), we investigated mTOR and its phosphorylation status in the cerebellum of AL treated Npc1 -/mice. Western blotting indicated that levels of mTOR and its phosphorylation on serine 2448 (Yanagisawa et al, 2017) (phosphorylated/total protein expression ratios (p/t)) were not changed by ADLL, ALL or ADL (Suppl. Fig.…”

Section: Potential Targets Of Leucine Analogues In the Cerebellummentioning

confidence: 99%

Acetyl-Leucine slows disease progression in lysosomal storage disorders

Kaya

Smith

et al. 2020

Preprint

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Acetyl-DL-leucine (ADLL) is a derivative of the branched chain amino acid leucine. In observational clinical studies ADLL improved symptoms of ataxia, in particular in patients with the lysosomal storage disorder (LSD), Niemann-Pick disease type C 1 (NPC1). Here, we investigated ADLL and its enantiomers acetyl-L-leucine (ALL) and acetyl-D-leucine (ADL) in symptomatic Npc1 -/mice and observed an improvement in ataxia with both enantiomers and ADLL. When ADLL and ALL were administered pre-symptomatically to Npc1 -/mice, both treatments delayed disease progression and extended life span, whereas ADL did not.These data are consistent with ALL being the neuroprotective enantiomer. Altered glucose and antioxidant metabolism were found to be implicated as one of the potential mechanisms of action of the L enantiomer in Npc1 -/mice. When miglustat and ADLL were used in combination significant synergy resulted. In agreement with these pre-clinical data, when NPC1 patients were evaluated after 12 months of ADLL treatment, rates of disease progression were slowed, with stabilisation or improvement in multiple neurological domains. A beneficial effect of ADLL on gait was also observed in this study in a mouse model of GM2 gangliosidosis (Sandhoff disease) and in Tay-Sachs and Sandhoff disease patients in individual-cases of off-label-use. Taken together, we have identified an unanticipated neuroprotective effect of acetyl-L-leucine and underlying mechanisms of action in LSDs, supporting its further evaluation in clinical trials in lysosomal disorders.

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“…reported that upregulation of SPNS1 regulates luminal solute compositions, thereby altering the subcellular distribution of lysosomes and the accumulation of p62 [43]. Dysregulation of autophagy lysosomes may promote the invasion and migration of HCC [44].…”

Section: Discussionmentioning

confidence: 97%

Identification of an Autophagy-Related Gene Signature that Can Improve Prognosis of Hepatocellular Carcinoma Patients

Huo

Huang

et al. 2020

Preprint

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Background: Autophagy is a programmed cell degradation mechanism that has been associated with several physiological and pathophysiological processes, including malignancy. Improper induction of autophagy has been proposed to play a pivotal role in the progression of hepatocellular carcinoma (HCC).Methods: Univariate Cox regression analysis of overall survival (OS) was performed to identify risk-associated autophagy-related genes (ARGs) in HCC data set from The Cancer Genome Atlas (TCGA). Multivariate cox regression was then performed to develop a risk prediction model for the prognosis of 370 HCC patients. The multi-target receiver operating characteristic (ROC) curve was used to determine the model’s accuracy. Besides, the relationship between drug sensitivity and ARGs expression was also examined.Results: A total of 62 differentially expressed ARGs were identified in HCC patients. Univariate and multivariate regression identified five risk-associated ARGs (HDAC1, RHEB, ATIC, SPNS1 and SQSTM1) that were correlated with OS in HCC patients. Of importance, the risk-associated ARGs were independent risk factors in the multivariate risk model including clinical parameters such as malignant stage (HR=1.433, 95% CI=1.293-1.589, P<0.001). In addition, the area under curve for the prognostic risk model was 0.747, which indicates the high accuracy of the model in prediction of HCC outcomes. Interestingly, the risk-associated ARGs were also correlated with drug sensitivity in HCC cell lines.Conclusion: We developed a novel prognostic risk model by integrating the molecular signature and clinical parameters of HCC, which can effectively predict the outcomes of HCC patients.

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L-leucine and SPNS1 coordinately ameliorate dysfunction of autophagy in mouse and human Niemann-Pick type C disease

Cited by 24 publications

References 40 publications

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

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

Acetyl-Leucine slows disease progression in lysosomal storage disorders

Identification of an Autophagy-Related Gene Signature that Can Improve Prognosis of Hepatocellular Carcinoma Patients

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