Molecular Mechanisms in Parkinson's Disease

Question 1

What is the most common initial symptom of PD?

Answer 1

Tremor

Question 2

What is the leading cause of death in PD patients?

Answer 2

Bronchopneumonia

Question 3

What is the nigrostriatal pathway?

Answer 3

Innervation of the dorsal striatum by dopaminergic neurons from the substantia nigra pars compacta

Question 4

What are the mesolimbic and mesocortical pathways?

Answer 4

Innervation of the nucleus accumbens and olfactory tubercle by ventral tegmental area dopaminergic neurons

Question 5

What are the functions of the nigrostriatal, mesocortical, and mesolimbic pathways?

Answer 5

Reward, emotional control, motivation, cognition, and motor behaviour

Question 6

Give at least seven factors involved in the pathogenesis of Parkinson’s disease

Answer 6

Oxidative stress, protein aggregation, ubiquitin-proteasone dysfunction, impaired dopaminergic neurotransmission, dysregulation of protein translatin, decreased neurotrophic signalling support, mitochondrial dysfunction, synaptic dysfunction, neuroinflammation, altered vesicle-organelle trafficking, impaired lysosome autophagy

Question 7

Damage to which pathway causes motor symptoms?

Answer 7

Nigrostriatal

Question 8

Damage to which pathway causes non-motor symptoms?

Answer 8

Mesolimbic

Question 9

What is the 26S proteasome in the ubiquitin-proteasome pathway formed from?

Answer 9

One 20S proteolytic complex and two 19S regulatory complexes

Question 10

Describe the ubiquitin-proteasome pathway

Answer 10

Ubiquitin is conjugated to a substrate. A chain targets the substrate to the 26S proteasome, where the substrate’s polypeptide chain is unfolded and translocated through a narrow pore to access the active sites in the interior of the 20S proteolytic complex. The substrate is hydrolysed into short polypeptides, and ubiquitin is recycled

Question 11

State at least 2 pieces of evidence for the involvement of reactive oxygen species (ROS) in PD

Answer 11

1) Dopamine and its metabolites have an intrinsic tendency to form ROS
2) The substantia nigra is rich in iron and copper, and the oxidation-reduction cycle of iron can generate free radicals and toxic metabolites
3) Mitochondrial abnormalities, leading to the uncoupling of redox reactions and generation of ROS, have been implicated in PD
4) The substantia nigra in PD may be deficient in antioxidants, e.g. glutathione

Question 12

How can mitochondrial dysfunction activate apoptotic pathways?

Answer 12

Mitochondria - damaged by the loss of membrane potential and increase in membrane permeability - release cytochrome c, which leads to formation of an apoptosome with procaspase 9 and Apaf-1

Question 13

Name the 2 main transcription factors involved in the development of midbrain dopaminergic neurons

Answer 13

Sonic hedgehog (SHH) and Fgf8

Question 14

Removing which late developmental factor causes the loss of function of dopaminergic neurons?

Answer 14

Nurr1

Question 15

Name 3 late development factors involved in the development of dopaminergic neurons

Answer 15

Nurr1, Foxa1, Foxa2

Question 16

Which developmental factor is involved in the degeneration of dopaminergic neurons in old age?

Answer 16

Foxa2

Question 17

Describe the effect of Engrailed deficiency on mice

Answer 17

Engrailed deficient mice develop dopaminergic neurons, but lose these neurons within 48 hours

Question 18

Name the Engrailed subgroup of mice which gradually lose their dopaminergic neurons in the substantia nigra only

Answer 18

En1+/- ; En2-/-

Question 19

What is the effect of engineering substantia nigra pars compacta neurons to expressed ventral tegmental area specific genes?

Answer 19

It is protective against pathology, suggesting that pro-survival genes are downregulated by the substantia nigra, leaving it inherently vulnerable

Question 20

Describe the changes to alpha-synuclein in Lewy bodies

Answer 20

The alpha-synuclein is hyperphosphorylated, ubiquitinated, and aggregated, making it insoluble

Question 21

Give at least 3 factors which increase the likelihood of alpha-synuclein aggregation

Answer 21

Genetic mutations, proteasome dysfunction, mitochondrial dysfunction, oxidative stress, phosphorylation

Question 22

What is parkin?

Answer 22

An E3 ligase which participates in the addition of ubiquitin molecules to target proteins, marking them for degradation

Question 23

What is the consequence of a loss of parkin function?

Answer 23

An inability to break down ageing or damaged proteins and organelles

Question 24

Do parkin mutations cause autosomal dominant or recessive familial PD?

Answer 24

Recessive

Question 25

Do PTEN-induced putative kinase 1 (PINK-1) mutations cause autosomal dominant or recessive familial PD?

Answer 25

Recessive

Question 26

Give 2 functions of DJ1

Answer 26

1) Inhibiting the aggregation of alpha-synuclein via chaperone activity, protecting the cell from oxidative stress
2) Modulating the mitochondrial membrane potential

Question 27

State the inheritance pattern of familial PD caused by mutated DJ1

Answer 27

Autosomal recessive

Question 28

How is PD caused by a DJ1 mutation distinguished from PD caused by PINK-1 or parkin mutations?

Answer 28

It is early-onset

Question 29

What is the consequence of PTEN-induced putative kinase 1 (PTEN-1) knockout in Drosophila?

Answer 29

Mitochondrial dysfunction, reduced respiratory chain activity, reduced ATP content of tissues, and increased propensity to apoptosis