Burke 2008 H&Y vs Braak Stage scatter plot, Calcium channels (Cav subtypes table), SN DA neurons / Isradipine / In PD notes, askIT / CDA email thread (start)

(Burke, 2008 #2004)

Fig. 3

• Y-axis: H & Y SCORE — ticks 0, 1, 2, 3, 4, 5
• X-axis: BRAAK STAGE — ticks 0, 1, 2, 3, 4, 5, 6
• Top sub-panel: SUBJECTS WITH PD
• Bottom sub-panel: SUBJECTS WITHOUT PD

Fig 3. Relationship between Braak PD Stage and Hoehn and Yahr PD score at the time of death in 96 individuals. The data presented are from Braak, 2003. The 68 individuals with a Hoehn and Yahr score of 0 are the same individuals as shown in Fig 2, with the single exception that Braak Case 105, with a diagnosis of Alzheimer’s, is excluded in Fig 2. Among 29 patients with PD (Hoehn and Yahr 1 or more), there is no relationship between Hoehn and Yahr score and Braak Stage (r = -0.2, NS). The data appears to be clustered into two populations: those with PD and those without.

Fig. 2

Fig. 2. Relationship between subject age at time of death and Braak PD Stage in 116 individuals without dementia or parkinsonism. The data presented are from Braak4, Parkkinen12, and Bloch44. There is no relationship between age at death and Braak Stage (r = 0.09, NS). Braak Stage 1 to 6 synuclein pathology is observed in neurologically unimpaired individuals who live decades beyond the average life expectancy at birth for industrialized nations.

(Burke, 2008 #2004)

Braak stage 4,5 의미:

• (braak stage 4,5,6 간에 H&y 가 전혀 차이 없기 때문에,) mild/moderate 논할 수 없음.
• braak stage 5,6 환자의 25-29% 는 H&y 3 (moderate) 가 있다.

age 외는 진짜 전혀 무관하구나.

Calcium

• Calcium channels
  • DA neurons are L-type calcium (Ca2+) channel-dependent autonomous pacemakers that, in the absence of synaptic input, generate rhythmic action potentials.
  • As discussed in recent reviews, 3,4 cells in which Ca2+ channels drive pacemaking may generally experience higher levels of basal oxidative stress due to ATP demands for intra-cellular calcium handling. But pacemaking may come at an especially high metabolic cost for DA neurons using Cav1.3 Ca2+ channels that open at relatively hyperpolarized potentials (as compared to the more common Cav1.2 channels).
  • Pharmacol Ther. 2012 Mar; 133(3)

Subunit composition and cellular location of voltage-gated calcium channel subtypes*.

Channel	Current	α1 subunit	Other subunits	Cellular location	Primary function
Cav1.1	L	S	α2δ, β, γ	Skeletal muscle, neuronala,b	Excitation-contraction coupling
Cav1.2	L	C	α2δ, β, γ	Neuronal (axon, soma, dendrites), cardiac and smooth muscle	Synaptic plasticity
Cav1.3	L	D	α2, β, δ	Neuronal (soma, proximal dendrites), sensory, smooth muscle	Pacemaking
Cav1.4	L	F	[β2]	Retina, spinal cord	Neurotransmitter release
Cav2.1	P/Q	A	α2δ, β, [γ]	Neuronal (presynaptic, soma, dendrites)	Neurotransmitter release
Cav2.2	N	B	α2δ/β1, β3, β4[γ]	Neuronal (presynaptic, soma, dendrites)	Neurotransmitter release
Cav2.3	R	E	α2δ/β [γ]	Neuronal (presynaptic, soma, dendrites)	Neurotransmitter release
Cav3.1	T	G	α2δ1, α2δ2	Neuronal (soma, dendrites)	Thalamic oscillations
Cav3.2	T	H	?	Neuronal	?
Cav3.3	T	I	γ2	Neuronal	Thalamic oscillations

*Data from (Catterall et al. 2005, ^aTakahashi et al. 2003, ^bSinnegger-Brauns et al. 2009), [ ] = putative, ? = unknown.

SN DA neurons

• use pacemaking voltage gated calcium channel (Cav1.3), rather than less energy demanding, monovalent cation channel
• {Chan, 2007 #1454} Adult SNc neurons are Ca2+ dependent. L-type channels in brain neurons have one of two α-subunits: Cav1.2 or Cav1.3. Because of their broad distribution and high affinity for dihydropyridines, channels with the Cav1.2 subunit have been the focus of most physiological work. These channels open only at relatively depolarized membrane potentials, making them poorly suited to the task of driving pacemaking.
• Channels with pore-forming Cav1.3 subunits have a more restricted distribution in the brain, have a low affinity for dihydropyridines and open at relatively hyperpolarized, sub-threshold membrane potentials, making them perfectly suited for pacemaking 20,21,22,23. SNc dopaminergic neurons robustly expressed Cav1.3 subunit messenger RNA (Fig. 1f), suggesting that channels with these subunits, and not those with a Cav1.2 subunit, underlie pacemaking in adult SNc dopaminergic neurons. (but Hurley actually shows equal expression of Cav1.2 & Cav1.3)

Isradipine

• {Ortner, 2017 #1455} During SN DA-like pacemaking, only Cav1.3 variants conducted Ca2+ current (ICa) at subthreshold potentials between action potentials. a 5- to 11-fold lower sensitivity to Cav1.3 variants during SN DA-like pacemaking compared with Cav1.2 during aSM-like activity

In PD

• {Hurley, 2013 #1452} autopsy, 혹시 i) PD환자들이, ii) SN DA neurone들이 원래 Cav1.3을 많이 가져서 (as a predisposing factor) ㅂ 발병하나 봤는데 아닌 걸로 나오네.

CDA / askIT email thread (start)

		askIT ticket		Me → supplier	Me → lisa
	Dear xxx. It was so nice talking to you at the introductory call. As I mentioned, I would like to proceed with Confidential Disclosure Agreement (CDA) to enable further scientific information exchange. If you agree, could you kindly provide your CV and the following information? Business Address, Please indicate if there will be an added signatory from your institution other than you. If yes, please provide the email. Best Jaewon	https://takeda.service-now.com/AskIT?id=nr_sc_cat_item&sys_id=3be7535d1b880114c897ff3ecc4bcb8c, Cost Center : 3160003827	- I have been assigned your ticket RITM1782178 request for Mutual CDA with Minee L. Choi and Takeda. Soon, I will follow with another email containing the Draft CDA and instructions. (from Lisa Cabeceiras) - Attached is a draft CDA for: Minee L. Choi. Please send it for review and comment to Minee L. Choi. Please ask that all changes are made using the track changes feature in MSWORD and return the redline back to me for legal review. If the CDA is acceptable "as is", and there are no changes, please confirm via email "okay as is", and I will prepare the CDA for execution via DocuSign. (from Lisa Cabeceiras) Dear Jaechul, Attached is a draft mutual CDA for review and comment. I have copied in Julie Boyle who drafted the CDA from our end. It will be appreciated if you comment/edit using the track changes feature in	Dear Prof. xxx. I hope you had a great weekend. Please review the attached CDA draft and see the request below from Takeda CDA management team. Once review is done then the signing will be executed via electronically – DocuSign. Hello Jaewon and Happy Monday! Attached is a draft CDA for: Minee L. Choi Please send it for review and comment to Minee L. Choi. Please ask that all changes are made using the track changes feature in MSWORD and return the redline back to me for legal review. If the CDA is acceptable "as is", and there are no changes, please confirm via email "okay as is", and I will prepare the CDA for execution via DocuSign. Please reach me	Hi Lisa, I can share with you that Choi has accepted the CDA as is. Best Jaewon → We currently are awaiting signature from Ceri Davies (from Lisa) ...assistance. Please let me know if you have any questions.

Uncertain Spans

location	transcription	uncertainty
Cav table / Cav1.3 row	α₂, β, δ	the legend / OCR shows α₂δ family across rows but the Cav1.3 cell is rendered with comma-separated α₂, β, δ; preserved verbatim.
CDA / Me → supplier cell	tail Please reach me	sentence is clipped at the bottom edge of the photo.
CDA / Me → lisa cell	tail ...assistance. Please let me know if you have any questions.	the leading word before assistance is clipped at left; preserved verbatim.