UK Biobank Top Differentially Expressed Proteins, Unmet Needs, And Start Of MOA Of UPS

UK Biobank — Top differentially expressed and decreased proteins for G20 Parkinson’s Disease Case-Control analysis (continuation)

		Direction	GeneName	ProteinName	Function	OR	P
Erin	1	Down	ITGAV	Integrin alpha-V	The alpha-V (ITGAV) integrins are receptors for vitronectin, cytotactin, fibronectin, fibrinogen, laminin, matrix metalloproteinase 2, osteopontin, osteomodulin, prothrombin, thrombospondin and vWF	0.60	1.4e-41
	2	Down	BAG3	BAG family molecular chaperone regulator 3	Co-chaperone for HSP70 and HSC70 chaperone proteins. Acts as a nucleotide exchange factor (NEF) promoting the release of ADP from the HSP70 and HSC70 proteins thereby triggering client/substrate protein	0.70	3.2e-21
	3	Down	HPGDS	Hematopoietic prostaglandin D synthase	Bifunctional enzyme which catalyzes both the conversion of PGH2 to PGD2, a prostaglandin involved in smooth muscle contraction/relaxation and a potent inhibitor of platelet aggregation, and the conjug	0.71	4.7e-20
	4	Down	CLEC10A	C-type lectin domain family 10 member A	Probable role in regulating adaptive and innate immune responses. Binds in a calcium-dependent manner to terminal galactose and N-acetylgalactosamine units linked to serine or threonine. These sugar	0.73	3.8e-17
	5	Down	ITGAM	Integrin alpha-M	Integrin ITGAM/ITGB2 is implicated in various adhesive interactions of monocytes, macrophages and granulocytes as well as in mediating the uptake of complement coated particles and pathogens (PubMed 9	0.74	6.9e-16
	6	Down	ITGA11	Integrin alpha-11	Integrin alpha-11/beta-1 is a receptor for collagen.	0.75	5.4e-15
	7	Up	NEFL	Neurofilament light polypeptide	Neurofilaments usually contain three intermediate filament proteins: NEFL, NEFM, and NEFH which are involved in the maintenance of neuronal caliber, additionally cooperate with the neuronal interm	1.30	4.8e-14
	8	Up	CD276	CD276 antigen	May participate in the regulation of T-cell mediated immune responses. May play a protective role in tumor cells by inhibiting natural-killer mediated cell lysis as well as a role of marker for detect	1.27	4.3e-10
	9	Up	EBI3_IL27	Interleukin-27	NA	1.27	9.2e-10
	10	Up	DDC	Aromatic-L-amino-acid decarboxylase	Catalyzes the decarboxylation of L-3,4-dihydroxyphenylalanine (DOPA) to dopamine, L-5-hydroxytryptophan to serotonin and L-tryptophan to tryptamine	1.18	7.0e-06
	11	Up	NCAM1	Neural cell adhesion molecule 1	This protein is a cell adhesion molecule involved in neuron-neuron adhesion, neurite fasciculation, outgrowth of neurites, etc.	1.19	1.4e-05
	12	Up	PSG1	Pregnancy-specific beta-1-glycoprotein	NA	1.17	3.9e-05

Unmet Needs

{Port, 2021 #1891} n=790 (이중 86%가 patient, 나머지는 family etc)

Fig. 1. Symptoms or side effects reported in response to the question “what aspect of Parkinson’s do you most wish to see improvement in?” presented by priority. Percentages show the relative frequency of symptoms or side effects reported within primary responses (n = 848), secondary responses (n = 779), and tertiary responses (n = 668).

Overall: (nonmotor 보다는 motor 가 우선이네) (상지는 tremor, 하지는 gait/fall 등) tremor, balance/fall/walking, stiffness/freezing, pain (cogniti

Fig. 2. Top 10 most frequently reported symptoms or side effects respondents wished to see an improvement in by disease duration. The area of the boxes show the relative frequency of the 10 most reported symptoms or side effects respondents diagnosed for (a) <2 years (n = 409), (b) 2–5 years (n = 648), (c) 5–10 years (n = 327) and (d) 11 + years (n = 86), wished to see an improvement in, where n is the total number of categorizable, symptoms or side effects reported. Responses from bereaved partners, family members or friends have been excluded as no duration data is available.

Fig. 3. Symptoms of Parkinson’s disease that were reported as a priority for improvement less frequently with disease duration. Percentages show the respondents with a duration of <2 years (n = 134), 2–5 years (n = 313), 6–10 years (n = 209) and 11 + years (n = 126) reporting (a) tremor, (b) stiffness, and (c) psychological health within their 3 priority areas. Statistical significant between duration groups (Dunn’s multiple comparisons tests) are presented as asterisks: *p < 0.05; **p < 0.01; ***p < 0.001; ****p < 0.0001. Responses from bereaved partners, family members or friends have been excluded as no duration data is available.

Fig. 4. Symptoms or side effects of Parkinson’s disease that were reported as a priority for improvement more frequently with disease duration. Percentages show the respondents with a duration of <2 years (n = 134), 2–5 years (n = 313), 6–10 years (n = 209) and 11 + years (n = 126) reporting (a) balance and falls, (b) walking, (c) speech, (d) freezing, (e) dyskinesia, and (f) medication wearing-off within their 3 priority areas. Statistical significant between duration groups (Dunn’s multiple comparisons tests) are presented as asterisks: *p < 0.05; **p < 0.01; ***p < 0.001; ****p < 0.0001. Responses from bereaved partners, family members or friends have been excluded as no duration data is available.

MOA of UPS

steps	description
Ubiquitin is activated by a ubiquitin-activating enzyme (E1) through an ATP-dependent mechanism	The E1 enzyme hydrolyses ATP and adenylates the C-terminus of ubiquitin, and then a thioester bond is formed between the active site cysteine of E1 and the C-terminus of ubiquitin.
The activated ubiquitin is transferred to ubiquitin-conjugating enzymes (E2).	The thioester-linked ubiquitin is then transferred from the ubiquitin-conjugating enzyme, E2, in an ATP-dependent reaction, forming another thioester bond to the active site cysteine of the E2 enzyme (Tsai, 2014).
E3 Ligase recognize a particular protein substrate → Then ligated to lysine residues of the protein substrates (in a reaction catalysed by many different ubiquitin protein ligases (E3).) Ub를 E2에서 뺏어서 protein substrate로 옮긴다.	ubiquitin is transferred from the E2 enzyme to a lysine residue on a substrate protein in a reaction catalysed by many different ubiquitin ligases, E3, which bind to specific substrate sequences, permitting the substrate specificity associated with this enzyme cf) there is >600 E3 ligases,
Additional ubiquitin molecules can be linked to the first one and form a poly-ubiquitin chain on the protein substrate with the help of a particular type of E3 ligase, as there are multiple lysine residues in ubiquitin that can be used to link ubiquitin molecules together

The ubiquitinated proteins are degraded by the 26S proteasome. The 26S proteasome is a large (>60 subunits) particle composed of a 20S barrel-shaped proteolytic core and two 19S regulatory “caps” at either end (McNaught et al., 2001). The 20S proteasome core consists of four stacked rings; the two outer rings contain seven distinct but homologous α subunits and the two inner rings contain seven homologous β subunits. In each β ring, three β subunits contain proteolytic sites, which face the inner chamber of the cylinder and cleave

Uncertain Spans

location	transcription	uncertainty
UK Biobank table	OR/P columns for rows 1-12	The numeric OR and P-value columns are read from the small-font right edge of the table; the values match the body_full crop but individual digits in 1.30/1.27/1.27/1.18/1.19 may need verification.
Fig. 1 caption	last clause tertiary responses (n = 668)	The figure-caption number 668 reads as printed; the trailing punctuation past the period is cut off in this capture.
Fig. 2 captions	small caption text (b) 2-5 years (n = 648), (c) 5-10 years (n = 327)	The numbers 648 and 327 reproduce the sample sizes printed beside each panel; the surrounding micro-text is small.
Overall red note	trailing pain (cogniti	The red overall summary line continues past the photo edge; the visible end is pain (cogniti and the closing parenthesis is not in this capture.