Postmortem tail, Odds ratios, Phenotype / Cognition GBA-PD, Gene Dose Effect, MOA GBA-PD

Postmortem GBA-PD (continued)

(Tsuang, 2012 #536)	heteroz	DLB,	16 vs 2 GBA+ DLB (N=18) % with cortical LB : 89% VS ? (안 나옴) %

Odds ratios

group	GlcSph plasma	OR	note	citation
Heteroz	No change (2011 Dekker)	3.2	(N370S, L444P 다 비슷함)	2015 Gan-Or
GD1 (N370이 대부분일 듯)	↑ 100 x (2011 Dekker)	2.2		2015 Gan-Or
GD2,3 (L444P가 대부분일 듯)		10.3		2015 Gan-Or

Phenotype of GBA-PD

citation	cohort	finding
(Kozlovski, 2019 #2343)	from 1525 Ashkenazi Jews with PD; 161 G2019S-LRRK2-PD, 222 GBA-PD, and 1142 iPD	Fig3) GBA-PD presented greater cognitive and autonomic involvement, more frequent hyposmia and REM sleep behavior symptoms while these were less frequent among LRRK2-PD compared to iPD.
(Thaler, 2018 #646)	GBA+PD: N=12, cognitively intact, GBA-PD: N=57, cognitively intact	이들 다 widespread cortical thinning 보이고, 두 군간 차이는 없음 (cognitively intact 니까 그렇겠지)

Cognition GBA-PD

citation	cohort / diagnosis	READout
(Oeda, 2015 #880) Utano National Hospital, Kyoto,	GBA+PD: N=49, GBA+PDD: N=14 (dementia Dx by DSM-IV), no DLB	HR (KaplanMeier curves of dementia), no v MRI
(Mitsui, 2009 #882), taku hatano 포함, multicentre	GBA+PD: N=49, GBA+PDD: N=13 dementia by clinical dementia rating ≥1	No MRI

Gene Dose Effect in PD

아래 표는 만들다 맘, but after all, the three most common GBA risk variants are not severe mutation 이잖아!

condition	GBA Protein	GBA activity	LB: GBA in LB	LB: Distribution	Onset	Progression
PD w GBA hetero	↓ 20-50%	↓ 17-58%	75% (thesis)	more diffuse distribution and in more atypical locations (the hippocampal regions CA2-4, (not localized in the brain stem and limbic system)(thesis)	50.0 (2015 Brockmann)	- 2015 Brockmann: [중요] Rapid over 3yr (motor etc) "Late acceleration": When does the process of rapid progression in GBA associated PD start? At the point of PD diagnoses, PD patients with and without mutations in the GBA gene appear clinically indistinguishable (mechanism: One explanation could be compensatory mechanisms in the first years of the disease sustained by the younger age.) → 중반되면 At the end of our observation period after 3 years, with disease duration of 8 to 9 years, (H&Y stage 3에 막 진입한 시기니까, stage 2 에서 발생했단 거네) the GBA-associated subgroup was more severely affected by motor impairment, disease staging, and cognitive decline. What might be the reason for this relatively late acceleration of disease progression in GBA1PD1? But at some point this system becomes overburdened, resulting in rapid progression. But at later stage: bidirectional impairment loop (ie Mazzuli), ie LB 가 GBA 를 impair 시키므로. (Winder-Rhodes, 2013 #179) the hazard ratio for progression both to dementia (5.7, P = 0.003) and Hoehn and Yahr stage 3 (4.2, P = 0.003) were significantly greater in GBA mutation carriers.
PD wo GBA mutation		↓ 19-33% (2012 Gegg)	<10%		60 (2015 Brockmann)	Steady over 3yr (2015 Brockmann)
PD w GBA homo
GBA hetero only		↓ 20% (2012 Kurzawa)

Gene dose effect:

• Hetero 중에서 L444P가 N370S 에 비해 onset, motor Sx 약간 심하거나 비슷하다.
  • PD중에서
    • GD/PD > GBA hetero/PD (L444P가 N370S보다 약간 심한 경향) (2018 Thaler) > PD only 순으로 onset, motor Sx 심하다. (2018 Thaler, 2017 Thaler, 이 둘은 GD+PD vs GBA+PD 비교 가능, 반면 2015 Gan-Or은 severe vs mild GBA mutation 비교만 가능한 듯)
    • Severe mutation vs Mild mutation
      • Severe mutation 이 Mild mutation보다 AAO 빠르다 (2015 Gan-Or), ↑ dementia (2016 Cilia)
      • The effect size was similar across all tested GBA variants (Blauwendraat, 2019 #32)

MOA GBA-PD

a-syn 유관

mechanism	Arguments	Counterarguments
↓ proteolysis → ↑ aSyn	[Mazzulli] (Fishbein, 2014 #100) Primary mouse cortical neuronal culture: (pulse chase analysis, Radiolabelled S35 methionine) L444P heterozygosity → ↓ (by 40%) GBA Activity → ↑ haSyn halflife (108 h vs 61h, fig 4A)
↑ GlcCer/GlcSph → ↑ a-syn Cf) GlcSph can readily exit the lysosome	In vitro: by direct interaction (Mazzulli, 2011 #160) in vitro, in acidic environment, increased (purified) GlcCer ① associated with misfolded (recombinant) a-syn, and ② increased (soluble oligomeric (purified recombinant) a-syn by delaying conversion to fibril form. ③ accelerated fibril assembly once this phase was initiated. [mechanism] GlcCer tubules provide a scaffold or platform for oligomeric intermediates to form that, once saturated, proceed to rapid polymerization of fibrils. (Taguchi et al. 2017, PMID 28847804) GlcCer & GlcSph → ↑ pathologic species (β-sheeted), ↑ (oligomeric) aggregation, ↑ fibrils	the vulnerability of specific neuron types is still not understood.
((Taguchi et al. 2017, PMID 28847804), 2018 Suzuki그림에는 GlcCer가 outside lysosoe에 많이 그려져 있음. Panel labels: E β-Sheeted WT α-Synuclein, G β-Sheeted A53T α-Synuclein. y-axis: β-Sheeted Structure (%). x-axis: Time (days). Series: PC / Cer / GlcCer / GlcSph / Sph / S1P.
In vivo: 이건 인과는 아님 (Zunke et al. 2018, PMID 29290548) GlcCer → oligomeric a-syn toxic assembly, (Suzuki et al. 2018, PMID 29305919) GlcCer → insoluble a-syn ((Huebecker et al. 2019, PMID 31703585) ↑ GlcCer/GlcSph → (↑ lipidation of a-syn ?) ↑ oligomeric a-syn (Taguchi et al. 2017, PMID 28847804) [GBA/PD mice] heterozygous Gba wt/SNCA tg (N_36), and homozygous Gba ko/SNCA tg GlcSph → pathologic species (β-sheeted, phosphorylated at S129, soluble oligomeric, aggregated). With age, brains exhibit glucosylceramide accumulations colocalized with -syn pathology. (Ikuno et al. 2019, PMID 30689867) GBA/PD model (gba heteroz KO + SNCA Tg): GlcSph (w/o GlcCer) → ↑ p-a-syn
aSyn:	(Kim, 2018 #609) GlcCer → ↓ tetramer (normally lipid binding is essential for sustaining the a-syn tetramer) & ↑ monomer intra-lysosomal cholesterol directly induce a-syn fibrilization (Bosco et al., 2006). Elevated levels of oxidized cholesterol metabolites in Lewy body disease brains accelerate a-syn fibrilization. Nat Chem. Biol. 2, 249-253.
p-aSyn ↓ ceramide → ↓ PP2A activity → ↑ p-aSyn	Ceramide is an activator of PP2A (Chalfant, 1999 #606)(Dobrowsky, 1993 #608) which functions as a dephosphorylation enzyme for a-syn.
aSyn ROS → ↑ a-syn oxidation → ↑ a-syn accumulation	oxidation and nitration of a-syn have been shown to impede clearance and stabilize a-syn oligomers in vitro (Hodara et al., 2004),
↓ GBA activity → dysfunction of endocytic pathway → ↑ exosome release, & ↑ exosome-associated aSyn oligomers release, → aSyn spreading	(Papadopoulos, 2018 #1273) normally, aSyn oligomeric species is found in exosomes. In vitro: GBA overexpression → ↓ exosome secretion in vivo: CBE in A53T-aSyn TG mice → ↑ intracellular aSyn oligomers, ↑ exosome release, ↑ exosome-associated aSyn goigomers release, [correction] virus-mediated expression of mutant GBA in the mouse striatum → increased ASYN secretion in the same region.
Vicious cycle, bidirecti	(Mazzulli, 2011 #160) in vitro: Overexpression of α-Syn Inhibits the Intracellular Trafficking of GCase → Resulting in Decreased Lysosomal GCase Activity
ceramide	Normal: ceramide binds cathepsin D and triggers its cleavage to the catalytic form [82], which is one of the main lysosomal enzymes responsible for a-syn degradation [83]. ↓ GBA → ↑ ceramide → ↓ mature cathepsin D → ↓ aSyn degradation
gangliosides ↓ GBA → ↓ Ceramide → ↓ GM1 → ↑ a-syn	(Forsayeth and Hadaczek 2018, PMID 29459819) a-syn binds GM1 tends to aggregate in the absence of ganglioside (Martinez et al., 2007). GM1 ganglioside levels in brain tissue from PD patients have been described (Wu et al., 2012; Hadaczek et al., 2015). (Forsayeth and Hadaczek 2018, PMID 29459819) Mice deficient with GM1a develop Parkinsonism
↓ GM1a → ↓ GDNF support	(Forsayeth and Hadaczek 2018, PMID 29459819, Huebecker et al. 2019, PMID 31703585)
Gain-of-function ↑ GBA → ↑ a-syn	(Yap et al. 2011, PMID) GBA interacts w a-syn
a-syn ↓ GBA activity → ↑ lipid accumulation → ↓ autophagy → ↑ a-syn	↓ GBA activity ↑ lipid accumulation → ↓ autophagy → ↓ mitophagy → ↑ OS (?)	Why only aSyn ↑ in PD? Why only pathologic species accumulated in PD? soluble nonphosphorylated

Uncertain Spans

location	transcription	uncertainty
Cognition / Oeda READout	no v MRI	reads as written; the leading v may be vMRI truncated.
MOA / Gain-of-function	(Yap et al. 2011, PMID)	the PMID number is not visible in this crop.