PD: Genetics and Epigenetics I

Question 1

Familial PD:

List some Parkinson’s associated proteins

Answer 1

• 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

Question 2

How have GWAS identified risk genes for idiopathic PD?

Answer 2

SNPs (single nucleotide polymorphisms) influence idiopathic PD expression

Many genes associated to familial PD

Question 3

Idiopathic PD:

Risk loci identified by GWAS?

Answer 3

• MAPT (tau)
• SNCA
• LRRK2
• GAK (cyclin-G associated kinase)
• HLA-DRB5 (MHC II)
• LAMP3
• (see ppt for more)

Question 4

What have GWAS identified about tau and PD?

Answer 4

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

Question 5

What is affected by SNPs?

Answer 5

• 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)

Question 6

Loci and relative risk for Familial PD?

Answer 6

SCNA- very rare, high risk

Question 7

Loci and relative risk for Idiopathic PD?

Answer 7

LRRK2- rare, medium risk

SNPs- common, low risk

Question 8

Principles of epigenetic control of gene expression?

Answer 8

• 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)

Question 9

Effects of HATs and HDACs?

Answer 9

HATs acetylate histones -> increased gene expression

HDACs de-aceytlate histones -> reduced gene expression

Question 10

Pathological epigenetic mechanisms in PD?

Answer 10

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

Question 11

Mechanism of how PD causes epigenetic changes?

Answer 11

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

Neuronal death due to reduced gene expression

Question 12

Use of valproate in PD?

Answer 12

General inhibition of HDACs

also an anticonvulsant

Question 13

Effect of lactacystin?

Answer 13

Proteosome inhibitor

[it is directly injected in nigro-striatal pathway]

Question 14

Unilateral Lactacystin model of PD outcomes?

Answer 14

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

Question 15

Effects of valproate on subjects?

Answer 15

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

Question 16

Genetic and molecular effects of valproate?

Answer 16

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

[neurorestoration is dose-dependent]

HIGH DOSE OF VALPROATE INDUCES S/E

Question 17

Future aims for epigenetic treatment of PD?

Answer 17

Potent, selective HDAC inhibitor