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GBA1 deficiency negatively affects physiological ?-synuclein tetramers and related multimers.

ABSTRACT: Accumulating evidence suggests that ?-synuclein (?-syn) occurs physiologically as a helically folded tetramer that resists aggregation. However, the mechanisms underlying the regulation of formation of ?-syn tetramers are still mostly unknown. Cellular membrane lipids are thought to play an important role in the regulation of ?-syn tetramer formation. Since glucocerebrosidase 1 (GBA1) deficiency contributes to the aggregation of ?-syn and leads to changes in neuronal glycosphingolipids (GSLs) including gangliosides, we hypothesized that GBA1 deficiency may affect the formation of ?-syn tetramers. Here, we show that accumulation of GSLs due to GBA1 deficiency decreases ?-syn tetramers and related multimers and increases ?-syn monomers in CRISPR-GBA1 knockout (KO) SH-SY5Y cells. Moreover, ?-syn tetramers and related multimers are decreased in N370S GBA1 Parkinson's disease (PD) induced pluripotent stem cell (iPSC)-derived human dopaminergic (hDA) neurons and murine neurons carrying the heterozygous L444P GBA1 mutation. Treatment with miglustat to reduce GSL accumulation and overexpression of GBA1 to augment GBA1 activity reverse the destabilization of ?-syn tetramers and protect against ?-syn preformed fibril-induced toxicity in hDA neurons. Taken together, these studies provide mechanistic insights into how GBA1 regulates the transition from monomeric ?-syn to ?-syn tetramers and multimers and suggest unique therapeutic opportunities for PD and dementia with Lewy bodies.

SUBMITTER: Kim S

PROVIDER: S-EPMC5789900 | biostudies-other | 2018 Jan

REPOSITORIES: biostudies-other

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GBA1 deficiency negatively affects physiological α-synuclein tetramers and related multimers.

Kim Sangjune S Yun Seung Pil SP Lee Saebom S Umanah George Essien GE Bandaru Veera Venkata Ratnam VVR Yin Xiling X Rhee Peter P Karuppagounder Senthilkumar S SS Kwon Seung-Hwan SH Lee Hojae H Mao Xiaobo X Kim Donghoon D Pandey Akhilesh A Lee Gabsang G Dawson Valina L VL Dawson Ted M TM Ko Han Seok HS

Proceedings of the National Academy of Sciences of the United States of America 20180108 4

Accumulating evidence suggests that α-synuclein (α-syn) occurs physiologically as a helically folded tetramer that resists aggregation. However, the mechanisms underlying the regulation of formation of α-syn tetramers are still mostly unknown. Cellular membrane lipids are thought to play an important role in the regulation of α-syn tetramer formation. Since glucocerebrosidase 1 (GBA1) deficiency contributes to the aggregation of α-syn and leads to changes in neuronal glycosphingolipids (GSLs) in ...[more]

PMID: 29311330

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Project description:About 10% of Japanese female athletes are afflicted by menstrually-related edema, mainly in the lower limbs, and, with few studies on this problem, the effect on performance remains unclear.To quantitatively evaluate fluid retention in the calf in female students over their menstrual cycle using magnetic resonance imaging (MRI) and to determine the relationship of MRI changes and athletic performance.The menstrual cycle was divided into 5 phases: menstrual, follicular, ovulatory, early luteal, and late luteal with sampling done in either morning (AM) or afternoon (PM) sessions. At each phase, MRI of the calf (7:00-8:00, 14:00-16:00), body composition and hormones (7:00-8:00), and athletic performance (14:00-16:00) were evaluated.13 adult healthy Japanese female students with eumenorrhea.Estradiol levels decreased significantly in the menstrual phase and the follicular phase compared to the early luteal phase (P = 0.001, P = 0.024 respectively). Menstrual phase estradiol levels were significantly lower compared to the ovulatory phase (P = 0.015), and the late luteal phase (P = 0.003). Progesterone levels decreased significantly in the menstrual phase and the follicular phase compared to the ovulatory phase (P = 0.012, P = 0.009 respectively), the early luteal phase (both P = 0.007), and the late luteal phase (P = 0.028, P = 0.029 respectively), and it along with a significant decrease in the ovulatory phase compared to the early luteal phase (P = 0.010). AM T2 signals were significantly lower in the menstrual phase compared to the ovulatory phase (P = 0.043) but not other phases. PM T2 signals increased significantly in the menstrual phase compared to the follicular phase (P = 0.003), ovulatory phase (P = 0.009), and the late luteal phase (P = 0.032), and the difference between the AM and PM values increased significantly in the menstrual phase compared to the other 4 phases (P<0.01). A negative correlation between fluid retention and agility was observed.In female students fluid retention during the menstrual phase could be a factor that influences athletic agility.

Dataset Information

GBA1 deficiency negatively affects physiological ?-synuclein tetramers and related multimers.

Publications

GBA1 deficiency negatively affects physiological α-synuclein tetramers and related multimers.

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