PD: Genetics and Epigenetics I Flashcards Preview

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Flashcards in PD: Genetics and Epigenetics I Deck (17)
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1

Familial PD:
List some Parkinson's associated proteins

- alpha synuclein
- LRRK2
- Parkin]- ubiquitin E3 ligase, linked to apoptosis regulation and damage mitochondrial turnover
- PINK1 (PTEN-induced putative kinase 1)]- protects cells from stress induced mitochondrial dysfunction -> autophagy
- DJ-1]- sensor for oxidative stress and stabilises mitochondrial membrane potential

2

How have GWAS identified risk genes for idiopathic PD?

SNPs (single nucleotide polymorphisms) influence idiopathic PD expression

Many genes associated to familial PD

3

Idiopathic PD:
Risk loci identified by GWAS?

- MAPT (tau)
- SNCA
- LRRK2
- GAK (cyclin-G associated kinase)
- HLA-DRB5 (MHC II)

- LAMP3
- (see ppt for more)

4

What have GWAS identified about tau and PD?

Tau is involved in disease pathology rather than just age-related changes in tau

5

What is affected by SNPs?

- Ubiquitin-prosome system (Parkin)

- Protein aggregation (SNCA, MAPT)

- Mitochondrial Clearance (Parkin, PINK1, DJ01)

- Protein-membrane trafficking (LRRK2, MAPT)

- Neuroinflammation & Complement (HLA)

- Synaptic function (SCNA, LRRK2)

6

Loci and relative risk for Familial PD?

SCNA- very rare, high risk

7

Loci and relative risk for Idiopathic PD?

LRRK2- rare, medium risk

SNPs- common, low risk

8

Principles of epigenetic control of gene expression?

- DNA methylation (physical blockage of DNA-> long term repression)

- Histone modification (short term repression, methylation/acetylation -> increased electrostatic repulsion of histones-> increased TF accessibility -> gene expression)

9

Effects of HATs and HDACs?

HATs acetylate histones -> increased gene expression

HDACs de-aceytlate histones -> reduced gene expression

10

Pathological epigenetic mechanisms in PD?

DNA methyltransferases (DNMT1) translocated out of nucleus -> hypomethylation -> changes in a-syn and PD risk genes

Histone modification of PD striatal neurons. A-syn accumulation promotes histone H3 hypoacetylation -> H3 is masked

11

Mechanism of how PD causes epigenetic changes?

Misfiled a-syn enters nucleus -> binds to histone H3 -> suppresses gene expression

Neuronal death due to reduced gene expression

12

Use of valproate in PD?

General inhibition of HDACs
(also an anticonvulsant)

13

Effect of lactacystin?

Proteosome inhibitor

[it is directly injected in nigro-striatal pathway]

14

Unilateral Lactacystin model of PD outcomes?

Lactacystin -> epigenetic changes (hypoacetylation -> decreased gene exp of BDNF, hsp70 and Bcl-2]- all usually aid neuronal survival)

15

Effects of valproate on subjects?

Neuroprotective (normalises forepaw behaviour and reduced amphetamine-induced rotation, higher TH

16

Genetic and molecular effects of valproate?

Reversed histone acetylation -> hyper-expression of BDNF, hsp-70, Bcl-2

[neurorestoration is dose-dependent]

HIGH DOSE OF VALPROATE INDUCES S/E

17

Future aims for epigenetic treatment of PD?

Potent, selective HDAC inhibitor