Animal models of GBA-PD tail, Correction studies (Rocha 2015 / AAV-A53T / Rockenstein 2016), S15 model, Sardi 2018 start

Animal models of GBA-PD (continued, A53T α-syn row)

	model	phenotype	injection / treatment	observation	quantification
	A53T α-syn Mouse, 4 month old	↓ GBA activity, ↑ a-syn, GlcCer/GlcSph 는 언급도 없음.	AAV striatum	Fig 4. GBA activity 10배증가 → aSyn 잘 뵈주면 반 감소	Fig 4 (4m post IX): cytosolic soluble α-syn (60±5% of control, n = 5, P < 0.01) by striatal expression of GBA (Fig. 4B). The membrane-associated α-syn also exhibited a modest reduction (81±9% of control, n = 5, P = 0.07) upon expression of GBA (Fig. 4B). However, the amount…

Correction studies

	model	phenotype	Injection of GBA	Transgene expression	Effect
(Rocha et al. 2015, PMID 26392287), GlcCer/GlcSph 는 언급도 없음	Thy-1-α-syn (line 61) Two- to three-month old 일명 ASO mice, TG human WT aSyn mouse 임.	(At 5 months of age ASO mice display a modest amount of α-syn pathology.) - no neurodegeneration	AAV2/5-(human) GBA1 into striatum, SN, hippocampus, 1회. The final titers for the vectors encoding human GBA1 and GFP were 2.0 × 1012 genome copies/mL.	Transgene expression of GBA1 was first confirmed at 8 months post-gene delivery in the substantia nigra (Fig. 3A), striatum (Fig. 3D) and hippocampus (data not shown) by IF 로 정량화 (density analysis) & WB 로 정량화함. Fig1c in SN: transgene expression 5배 증가	↑ GCase activity and ↓ accumulation of α-syn in SN & striatum. Prevention, young mice: at 5 m, (3 m post injection 이겠) 40% reduction in HMW (soluble oligomeric) α-syn oligomeric species (by WB) in the SN and ↓ in the striatum in comparison to AAV-GFP injected mice (Fig. 2B). Fig1c in SN: GBA activity 2배 증가 aSyn oligomer 절반 감소. Fig2: In SN & Striatum ↑ LC3II. Fig3. Therapeutic, old mice 10-11 m of age (8-m post-gene delivery): reduced the number and size of the proteinase-K resistant insoluble α-syn aggregates (staining) in SN and striatum. In SN: transgene expression ? 안나온듯 → GBA activity ? 안나온듯 → aSyn oligomer 전반 감소.	PD only model
	AAV-A53T mouse	selective dopamine neuron degeneration	AAV-(human) GBA1 into SN (co-injection with AAV-A53T α-syn into SN), 1회. AAV2/2-GBA1 and AAV2/2-A53T-α-syn vectors containing the coding sequences for the human GBA1 gene and for the human α-syn gene, respectively, were co-injected into the substantia nigra in the same injectate, at a final titer of 2.0 × 10? genome copies/mL.	At 24-weeks post-AAV injection, the transgene expressions of the viruses remained elevated in the dopamine neurons of the substantia nigra (Fig. 4D). 결국 우측 요약: Gba activity 2배 증가 → 정상대비 반이었던 SN neuronal loss 를 normalize함	Fig4 - ↑ GBA protein level (매우 많이, 이건 Transgene 만 본듯) - ↑ Gba activity (WT 이니 원래 정상수준인 gba ACTIVITY에서 약 2.5배?) - prevented nigrostriatal DA degeneration (50%) by 6 m (vs rats w AAV-GFP), AAV-GFP+A53T α-Syn RATS 에 비해선 30% Reduction 으로 보임 (원문에 comparable이라네) fig5보니 normalize라고 말할 수 있겠음 - ↓ α-syn accumulation (6 m post injection, but no data shown) - FIG6, in SN, restored (ie prevents) p62 (ie ↑) LC3II & LAMP2 는 원래 질환모델에서 불변, in Striatum restored (ie prevents) LC3II (↑), p62는 model에서 불변인데도 올림, LAMP2는 원래 질환모델에서 불변,	PD only model
(Rockenstein et al., 2016), GlcCer/GlcSph 는 결과에 언급도 없음	Thy1-α-Syn (line 61) js: 이건 WT a-syn overexpressing mice 임 + CBE		AAV-GBA into the bilateral striatum at 2 m of age	Immunostaining for glucocerebrosidase showed robust striatal expression in AAV1-GBA1-injected Thy1-SNCA mice at 9 m of age.	[at 9 m of age, ie 7 m after injection of AAV1-GBA] - ↑ GBA activity (×6) - ↓ (28%) total α-syn, ↓ (40%) proteinase K-resistant α-syn, amelioration of behavioral aberrations - protection from loss of striatal dopaminergic markers (DAT and TH, 둘다 원 모델의 30% loss를 거의 WT수준으로 막음)	gba+PD model

S15 model comparison

	WT	질병 Model GBA-PD 모델		질병 Model GBA+PD 모델		치료 Model GBA-PD 모델	치료 Model GBA+PD 모델
	WT	GBA+/L444P	WT+MPTP	GBA+/L444P +MPTP	GBA+/L444P +MPTP+SNCA KO	WT+MPTP+AAV/GBA	GBA+/L444P +MPTP (ip)+AAV/GBA
GBA activity		↓ (-20%)
GBA protein		↓ (-30%)
A-syn		↑↑ (+38.6%)	↑	↑↑		=	↑ (suppl fig 8, by WB, IHC in midbrain)
mitochondria		↓ (size, MC I activity, respiration)
ROS		↑
UPS		↓
DA Neuron		=	↓↓	↓↓↓	↓	↓	↓
GFAP		=	↑↑	↑↑↑	↑
DA turnover		=	↑↑	↑↑↑	↑
DOPAC & HVA		=	↑↑	↑↑↑	↑
TH fiber density		=	↓↓	↓↓↓	↓	↓	↓

Sardi et al. 2018, PMID ?

Sardi et al. 2018, PMID ?	Gba1 D409V/D409V mice	↓ GBA activity, ↑ α-syn	AAV1-recombinant GBA, bilateral hippocampus, at 4 m (prevention model) & 12 m (symptomatic model) of age, sacrificed 6 m postinjection. AAV-EV: Virus containing no GBA	아래는 12m에 injection model. Transgene expression 은 fig 2A 그림이고 정량화 안함. ↓ GlcSph (fig2, 반이니, 50%에서 포화된다는), ↓ proteinase K-resistant α-syn aggregates. WT+GT는 무자료	GD model

GlcSph (fig2)→ 20%

Uncertain Spans

location	transcription	uncertainty
AAV-A53T row / titer	at a final titer of 2.0 × 10<sup>?</sup> genome copies/mL	the exponent value is too small to read on this capture and is preserved as ?.