Lewy Body / components / Two types / Toxic mechanisms / Lewy neurites, Lipid-aSyn interaction review, Mutations SNCA, Neurodegeneration and aSyn (Mori 2006 + Lee 2017 staging table), DBM, Oligodendrocytic aSyn, PET aSyn vendor matrix start

Lewy Body

• Location
  • Inside neurons
• Components
  • an eosinophilic cytoplasmic inclusion consisting of a dense core surrounded by a halo of 10-nm-wide radiating fibrils,
  • the primary structural component is alpha-syn that is insoluble and polymerized, and modified by phosphorylation (Zhou, 2011 #602); most aSyn in LB is phosphorylated at serine 129, ubiquitination and nitrosylation also reported.
• components of LB / aB are also discovered

Component	Function
Microtubule-associated proteins, members of the chaperone network (e.g., HSPs) and UPS (e.g., ubiquitin activating, conjugating, ligating enzymes)	part of the cytoskeleton
Ig-3-3-3 (Giulio 2021 #2246)	Protein homeostasis (i.e., proteostasis)
Ubiquitin
alpha-Synuclein	Physically bind to a-syn in cells
Tau
parkin and its substrate
aminoacyl tRNA synthetase complex-interacting multifunctional protein-2 (AIMP2)	α-syn aggregation (Han, 2020 #1144)

Two types of LBs

α-syn 일컬	brainstem: a dense core of fibrillar Aβ and granule material, which is surrounded by a halo formed of radially oriented fibrils,
	Cortical: lack a distinctive core and halo.

Toxic mechanisms

• impairment of mitochondrial function, disturbance of intracellular protein homeostasis, chronic endoplasmic reticulum stress, formation of pore-like structures with perforation of membranes including the plasma membrane of neurons (7), and glutamate receptor dysfunction.

Lewy neurites

• abnormal neurites in diseased neurons, containing granular material and abnormal α-syn filaments similar to those found in Lewy bodies (1)
• neurite or neuronal process refers to any projection from the cell body of a neuron. This projection can be either an axon or a dendrite.

Lipid-aSyn interaction

review (Killinger, 2019 #2312)

Mutations SNCA

Five missense mutations causing familial PD: A53T, A30P, E46K, H50Q, G51D and A53T7

mutations:

• missense mutations,
• multiplication (triplication or duplication) of the entire SNCA locus has been demonstrated to cause familial autosomal dominant PD [6-8]; replication or triplication of α-syn is sufficient to cause PD

Three point mutations: A53T amino acid substitution in the locus, A30P, E46K

Others

• H50Q, G51D, A53E

Neurodegeneration and aSyn

(Mori, 2006 #1840) - in PD some normal (ie pigmented) neurons in SN and LC in PD ARE MORPHOLOGICALLY NORMAL despite having LB (a-syn deposit) in their cytoplasm (Table A); 10% in SN, 50% in LC [1]; there is no such neurons in normal control 가까이 그 (?); that bulb in cortex 일컬 일정 어림 in PD without LB.

(Lee, 2017 #1772) temporal sequence (Walker 2014 #604)	unified staging system / pathol-in cingulate & temporal cortex (WB biomarkers)	only LN	insoluble monomer (or limbic dominant)	III-Brain stem & limbic dominant	IV neocortical
cytosol enriched, monomer (a-1)	1	monomer	1
membrane enriched, monomer	1
HMW (soluble)	1
HMW (insoluble)	1
Insoluble monomer	1
Insoluble HMW	1
@ FC, brainstem/dorsal raphe inclusions and pyramidal & nigricolic project layers	2.6 4.8 5-7-9 0.5/1 0.18 2.5 ; 1.11			1
congulate & temporal cortex	0	0	0	1
Braak stage	1	1	1	1
LN argyrophilic acidic	1	1	1	1

DBM, Deformation-Based Morphometry: a method for identifying macroscopic anatomical differences among the brains of different populations of subjects. The method involves spatially normalizing the structural MR images. Characterization using DBM can be global, pertaining to the entire field as a single observation, or can proceed on a voxel by voxel basis to make inferences about regionally specific positional differences.

Oligodendrocytic aSyn

review (Killinger, 2019 #2312? this incorporates IF)

PET aSyn

we have an ongoing due diligence with ACI that includes small molecule therapy and α-syn PET so unfortunately communicating specific details outside that recipient is a bit restricted for now

As I can say based on what we’ve discussed with them at HAI on January (poster attached) is that 15916 is their next generation tracer to fill the PD gap. Their synthesis is that lower pathology expression in PD is what drives the lack of signal of 12589 so they are looking for candidates with higher PDsd. It remains to be seen if Bristol/Rabotin et al. Kd ratio of 4 is enough. Notice that the Kd for both compounds is in the 10s nM range. I’m sure Paull would agree that that is less than ideal. Additionally, a small molecule with such high selectivity over αSyn and tau however that will have to be scrutinized further specially if 15916 comes from the same chemical series as 12589. The key data shows a lower preference of 15916 compared the SR9. They are planning 916 IND and FIH by the end of 2024.

If our deal goes ahead, we might have the opportunity of considering using 15916 provided there is seminal data proving signal in PD by 2025. The total amount of abnormal α-synuclein protein was reported to be approximately 50-200 nM in the brainstem and subcortical regions of advanced DLB and MSA which was more than 10-fold smaller than the amount of Aβ peptide deposited in the brain of AD patients 48.

어 sensitive detector of early-stage Lewy pathologies, a compound with IC50 below 1 nM might be needed.

PET aSyn vendor matrix

	AC Immune	MODAG	University of Zurich	QST (Takeda, QST, Eisai, and Ono)	Shenzhen	Merck	Mass Gener at Brigham
	ACI-3847 / ACI-12589 / ACI-15916	SPAL-T-6		C05-05 / SPAL-T-95	FOSO28	MK-7337
	Pbb3 (a tau protein pet tracer)			benzothiazole-benzofuran-phenol derivative
	(Smith, 2023 #2765), Not found in cortells	NYBB 2023/0840 wo etc		FY2020 4Q FH DLB/PD w/ or w/o A6 and tau Not prioritized FH (One 2021 #2305); A FH to begin in 2023; preparation tracer for use
Morphomer platform 일정 thioflavin (oligo) PFF (recombinant 일정) oligomers with 2-6 nM	bind fibril forms of α5 but not soluble monomeric form because the series comes from β-sheet binder candidate 잡고 PFF (오리고머 fibril/Monomer ratio etc); Monomers; Brigham screening aSyn PFF candidate aSyn PFF tracer In to humans 2023
In vitro Patient brain — Current status / IF / Saturation (tracer / Competition binding assay (PATIENT) / Saturation / PD / Brain)

Uncertain Spans

location	transcription	uncertainty
Lee 2017 staging table	column-to-cell alignment for cytosol enriched, membrane enriched, HMW soluble, HMW insoluble, Insoluble monomer, Insoluble HMW rows	reads as written; the dense numeric-cell layout is reconstructed from the visible cells and may need image-level review.