Disease cascade tail, Glycolipid metabolism, GBA1 / GlcSph cycle, GBA chaperone / GCS inhibitor, GlcSph section

Ganglioside / sphingolipid degradation cascade tail (figure labels)

• Globoside arm continuing from the previous capture (clipped at top edge).
• Cerebroside (Ceramide–Gal) arm: Ceramide–Gal → Ceramide via β-galactosidase (releasing Gal).
• CholinePCeramide ↔ Ceramide via sphingomyelinase, disease Niemann-Pick disease; co-product Phosphocholine. (Sphingomyelin label visible at the right edge.)
• Ceramide → Sphingosine + fatty acid via ceraminidase, disease Farber's disease.
• Cerebroside arm: Ceramide–Gal → Ceramide via Gal-cerebroside-β-galactosidase, disease Krabbe's disease (releasing Gal).
• Sulphatide arm: Ceramide–Gal → Ceramide–Gal~S (Sulphatide) via cerebroside sulphatase, disease metachromatic leucodystrophy, side group SO₄²⁻.

위 그림에서 cerebroside 는 = GlcCer, GalCer

Glycolipid metabolism schematic

Visible chemical-structure schematic labels and arrows:

• Glucosylceramide ↔ Ceramide via GluCer synthase (forward) / GCase (reverse)
• Galactosylceramide ↔ Ceramide via GalCer synthase (forward) / GalCeramidase (reverse)
• Glucosylceramide → Lactosylceramide via LacCer synthase
• Lactosylceramide → Gangliosides via Sialyl Transferase
• Ceramide ↔ Sphingomyelin via SMase (Sphingomyelin → Ceramide) / SMS (Ceramide → Sphingomyelin)

Caption (under the figure):

Ceramide and glycolipid metabolism. Products are indicated in bold and italics. Abbreviations for enzymes are as follows: GCase: ; GalCer synthase: galactosylceramide synthase; GluCer synthase: glucosylceramide synthase; GalCeramidase: galactosyl synthase: Lactosylceramide synthase; SMase: Sphingomyelinase; SMS: Sphingomyelin synthase.

…/journal.pone.0073094.g001

GBA1 / GlcSph cycle inset

GlcSph inset figure labels:

• GlcCer ↔ GlcSph (annotated (C 18:0))
• GlcCer ↔ GlcCho ↔ GlcSph
• GalSph ↔ GalCer (annotated (C 24:1))
• GalCer ↔ Cer ↔ Sph
• GBA1 enzyme rectangle, EC 3.2.1.45, gating the GlcSph → GlcCho and Cer → Sph reactions
• Filled red ↑ and hollow ↑ arrows annotate disease-level direction beside GlcSph, GalCer, GlcCer, Cer, and Sph

GBA chaperone to increase GBA functions

Chaperone box figure labels and structures:

• Isofagomine (GD, failed in Ph-2) — chemical structure with HO, NH, OH groups on a ring.
• Ambroxol (GD/PD, Ph-2) — chemical structure with two Br substituents on an aromatic ring, an NH₂ amine, and an HO-N alkyl tail.

Reaction cartoon below the chaperones:

• GluCer (skeletal structure with Sphingosine + fatty acid + Glu sugar) + GBA → Glucose + Ceramide
• Reverse arrow labelled GlcCer synthase (GCS)

GCS inhibitor

• Venglustat/Ibiglustat (GD/PD, Ph2) — chemical structure with a pyridine-carbamate linker, a thiazole and a 4-fluorophenyl group.

GlcSph

• 다음 둘 다 존재
  • glucosylsphingosine 는 glucosylceramide 로부터 생성되며 (by acid ceramidase, which can then exit the lysosome) ,
  • 따라서, GlcSph accumulates before GlcCer in murine GBA-PD brains [32], which agrees with our human SN data on 70s versus 80s cohorts PD subjects. (쌓여지려는 GlcCer 가 GlcSph로 acid ceramidase 에 의해 전환되므로).
  • GBA 의 substrate 인 것도 맞음 (GBA converts glucosylsphingosine to glucose and sphingosine, 이 경우는 GBA loss 시 GlcSph는 lysosome 내에 쌓이겠지?)

Glucocerebrosidase wheel figure labels:

• Glucosylceramide (Glucocerebroside)
• Glucosylsphingosine
• Glucocerebrosidase (central ellipse)
• Ceramide
• Glucose
• Sphingosine

Visible sphingolipid pathway labels (vertical tree):

• Sphinganine → (Dihydroceramide synthase) → Dihydroceramide → (Dihydroceramide desaturase) → Ceramide
• Ceramide ↔ Sphingomyelin via SM synthase / Sphingomyelinase (Niemann-Pick A/B)
• Ceramide → Sphingosine via Ceramidase (Farber disease)
• Galactosyl-cerebroside ↔ Ceramide via Ga/Cer synthase / β-galactosidase (Krabbe disease)
• Ceramide ↔ Glucosylceramide via GlcCer synthase / Glucosylceramidase (Gaucher disease)
• Glucosylceramide → Lactosylceramide → Complex glycosphingolipids

assay development

	Conventional	Can not detect GlcSph in CSF & plasma
	Highly sensitive	Not performed

Reference values of GlcSph

Method: Reference values were determined on normal controls (average +2*STD) Cozma, 2018 #826)

Normal range

• CSF
  • CSF <10.0 pg/mL (from n=37 control) (Narita 2016) js, this should be 2^nd referencing and I haven’t tried finding the original source.
  • CSF: CSF reference range: ≤ 0.0029 ng/ml (Charkhand, 2019 #527) js, this should be 2nd referencing and I haven’t tried finding the original source.
  • Tottori Univ disease controls: GlcSph was below LLOQ in 4 of 9 samples
  • NCNP analysis: GlcSph was below LLOQ in 32 of 50 samples, (but currently under remeasurement by LC/MS because technical problem was doubted).
• Blood
  • normal controls (average +2*STD) at <1.2 ng/mL (plasma) and <4.8 ng/mL (dried blood spots),. Cozma, 2018 #826)
  • plasma: (Murugesan, 2016 #845) in healthy controls on average was 1.5 ng/ml (1.3 - 1.7; 95% CI). LC-MS/MS,
  • Pathological range: 23.2 to 226.0 ng/mL (plasma) and 25.4 to 2853.0 ng/mL (DBS). Cozma, 2018 #826)

Uncertain Spans

location	transcription	uncertainty
GBA1 inset	GBA1, EC 3.2.1.45	OCR alternated between 8.11.45, 81145, and 3.2.1.45; the visible decimal places match the GBA EC number 3.2.1.45.
GlcSph notes	trailing 이 경우는 GBA loss 시 GlcSph는 lysosome 내에 쌓이겠지?)	small Korean text crosses tile boundaries; preserved as visible.