Transcranial sonography tail and Transcriptomics in PD

Transcranial sonography in PD

{Booth, 2015 #1745} REVIEW

Transcranial sonography reveals hyperechogenicity of thesubstantia nigra (Fig 5), which, together with normal echogenicity of the basal ganglia, has a positive predictive value of 93% for a prospective PD diagnosis.27 An advantage of transcranial sonographyis that these findings may also be premotor biomarkers.28 However, a disadvantage is that up to 20% of white and 60% of Asians cannot be studied due to an inadequate temporal acoustic bone window.

Transcriptomics in PD

Overview of transcriptomics in PD

		results	limitation
{Nido, 2020 #1310}2nd	A recent systematic review [8]. identified 33 original genome-wide transcriptomic studies in the PD brain, Of which 5 were performed on laser microdissected neurons from SNc) and the remaining in bulk tissue from various brain regions	The most consistent alterations have been found in pathways related to energy metabolism / mitochondrial function and protein degradation, followed by synaptic transmission, vesicle trafficking, lysosome / autophagy and neuroinflammation [8].	surprisingly low replicability at the level of individual genes, however, and only partial concordance for pathways. Confounding factors: Postmortem RNA degradation: {Jaffe, 2017 #1807} different cell types exhibit different degrees of susceptibility to RNA degradation. 아래 표보면, 두 방법 (ribo & PolyA) 의 microglia의 relative proportion 이 늘겠네. Cell Type # Genes Degradation T-stat Shift Enrichment P-value Ribo Astrocytes 224 -3.438 1.12E-41 *** Endothelial 190 -3.700 4.77E-41 *** Microglia 186 -1.675 1.77E-09 * Neurons 244 -2.830 3.26E-31 *** Oligodendrocytes 222 -2.132 6.16E-17 ** OPC 126 -0.650 5.41E-02 PolyA Astrocytes 222 -1.006 5.67E-04 * Endothelial 196 0.816 8.57E-03 * Microglia 180 0.309 3.40E-01 Neurons 241 -1.750 4.41E-10 ** Oligodendrocytes 221 0.114 6.96E-01 OPC 101 -0.316 4.64E-01 Table S4: Comparison of cell type specificity of degradation effects by library and cell type. Cell type heterogeneity: increased glia-to-neurons in PD patient

Bulk tissue transcriptomics in PD

{Nido, 2020 #1310}2nd

A recent systematic review[8]. identified 33 original genome-wide transcriptomic studies in the PD brain, Of which 5 were performed on laser microdissected neurons from SNc) and the remaining in bulk tissue from various brain regions

Single cell transcriptomics in PD

		Clustering	DEG		Functional enrichment analysis	Response to Perturbation
			upregulated	Downregulated		Rotenone Tx	Tunicamycin (ER stress0	SNCA-A53T heterozygous (A53T mutant iPSC)
Postmortem brain	{Nido, 2020 #1310}2nd		A recent systematic review[8]. identified 33 original genome-wide transcriptomic studies in the PD brain, Of which 5 were performed on laser microdissected neurons from SNc) and the remaining in bulk tissue from various brain regions
Postmortem brain	{Nido, 2020 #1310} sPD (n of 49), pre-frontal cortex		Common gene expression signatures in PD are driven by changes in cell composition (ie neuron줄고 microglia, oligodendrocyte, astrocyte 느는 것이 DEG에 반영될 뿐이니, 이는 confounding 이다, PD vs HC 시에)		(Before compensate for cell type composition) vesicle trafficking, synaptic transmission, immune, mt function → (after compensating cell type heterogeneity) ER, lipid oxidation, UPR
Postmortem brain	{Smajić, 2020 #1812}		6PD, 5 control: Cell composition change: ↑ microglia (showing a specific pro-inflammatory trajectory) ↑ astrocyte, ↓ oligodendrocyte, ↓ DA neurons
Postmortem brain	다음 두논문 사실 같은 것인데, #2054가 더 final version 임. {Smajić, 2022 #2053} {Smajić, 2021 #2054} midbrain, all cell types 6PD, 5 control:		cell fraction ↑ microglia, ↑ astrocytes, ↓ oligodendrycytes, no loss in the number of DaNs in the IPD, DaNs comprised 0.18% of total cell, but ↓45.9% in neuromelanin-positive nigral DaNs in PD patients vs HC. PD-microglia revealed a specific pro-inflammatory trajectory (FIG3, ↑GPNMB, ↑IL1B, ↑HSP90AA1). Microglia activation trajectory spans from P2RY12high cells towards two activation branches, one containing GPNMB high cells and another with cells highly expressing HSP90AA1 or IL1B (subpopulation 이라고 하네) (Fig. 3C). less ramified microglia in IPD, Finally, we discovered a neuronal cell cluster exclusively present in IPD midbrains characterized by CADPS2 overexpression and a high proportion of cycling cells. We conclude that elevated CADPS2 expression is specific to dysfunctional dopaminergic neurons, which have lost their dopaminergic identity and unsuccessful attempt to re-enter the cell cycle, Reactive astrogliosis specifically in patient cel		pathway analyses highlighted cytokine signalling and, likely upstream of this, an induction of the UPR pathway. We also found chaperones and heat-shock proteins overexpressed along the disease trajectory, which when they are released from the cell can act as damage-associated molecular patterns (DAMPs
Postmortem brain	{Anderegg, 2015 #1314} DA neurons from neonatal (normal!)	Cluster 1 & 2	Midbrain DA neurons show different transcriptome among different sub-regions (ie SN vs VTA)
Postmortem brain	MapPD Nicholas Wood (UCL); Sonia Gandhi (UCL), Steven Lee (University of Cambridge), Michele Vendruscolo (Univ of Cambridge)	in iPSC models and human brain tissues	oligomer map of the PD brain over 11 disease-relevant regions and over different cell types, → 이 map에서 oligomer-containing cell을 골라 → LCM (laser capture microdissection)으로 single cell 빼내 → sc trnscriptomics. genomics (ie SNP발굴, 이것도 oligomer-containing인지 불언급) - validation: iPSC+oligomer → readouts: ROS, mito, Ca, synapse, UPR, oligomer flux
vitro	{Fernandes, 2020 #1296} iPSC-derived (js: not sure if this fro PD patients, probably not) human dopamine neurons, differences in gene expression profiles between these closely related populations of neurons th	DAn1	In DAn1 neurons, top DEGs included genes associated with dopamine neuronal lineage (LMO3, POU2F2, NR4A2, LMX1A, DDC, and DRD2) and genes associated with PD (MAPT, SNCA, UCHL1, and ATP13A2) addition, we found upregulation of BDNF and genes involved with cytoskeleton dynamics and neuron projection, including members of the stathmin family (STMN2, STMN1, andSTMN4) and tubulin genes (e.g., TUBB2A, TUBB2B		synaptic signaling and vesicle trafficking (Figures 2A, 2C, and 2D)
		DAn2	DAn2 neurons presented with upregulation of genes associated with oxidative phosphorylation (e.g., MT-CO1, MT-ND3, COX17) exocytosis, apoptosis, response to OS (e.g., CST3, PON2, SEPP1) and ER stress		synaptic signaling, neuron projection, cell death regulation, and cholesterol biosynthesis, with SNCA and MAPT being among the top downregulated genes (as opposed to DAn1 neurons)
	{Lang, 2019 #1308} iPSC-derived human dopamine neurons, with N370S
N370S	{Novak, 2020 #1311} human PINK1-PD dopaminergic iPSC	했긴 했으나, differentiation stage 보려고 한 듯.	28 genes	27 genes	ubiquitination, mitochondrial, protein processing, RNA metabolism, and secretory pathways (all upregulated?)
	MapPD Nicholas Wood (UCL);	in iPSC models	oligomer map of the PD brain over 11 disease-relevant regions and