Molecular Mechanisms in Parkinson's Disease Flashcards
Critically evaluate the processes involved in development and normal survival and maintenance of dopaminergic neurons, including transcriptional regulation of neuronal development and survival and mitochondrial energy metabolism Critically evaluate the molecular mechanisms that may contribute to the vulnerability of midbrain dopaminergic neurons, including oxidative balance and stress, synaptic function, and protein handling
What is the most common initial symptom of PD?
Tremor
What is the leading cause of death in PD patients?
Bronchopneumonia
What is the nigrostriatal pathway?
Innervation of the dorsal striatum by dopaminergic neurons from the substantia nigra pars compacta
What are the mesolimbic and mesocortical pathways?
Innervation of the nucleus accumbens and olfactory tubercle by ventral tegmental area dopaminergic neurons
What are the functions of the nigrostriatal, mesocortical, and mesolimbic pathways?
Reward, emotional control, motivation, cognition, and motor behaviour
Give at least seven factors involved in the pathogenesis of Parkinson’s disease
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
Damage to which pathway causes motor symptoms?
Nigrostriatal
Damage to which pathway causes non-motor symptoms?
Mesolimbic
What is the 26S proteasome in the ubiquitin-proteasome pathway formed from?
One 20S proteolytic complex and two 19S regulatory complexes
Describe the ubiquitin-proteasome pathway
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
State at least 2 pieces of evidence for the involvement of reactive oxygen species (ROS) in PD
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
How can mitochondrial dysfunction activate apoptotic pathways?
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
Name the 2 main transcription factors involved in the development of midbrain dopaminergic neurons
Sonic hedgehog (SHH) and Fgf8
Removing which late developmental factor causes the loss of function of dopaminergic neurons?
Nurr1
Name 3 late development factors involved in the development of dopaminergic neurons
Nurr1, Foxa1, Foxa2
Which developmental factor is involved in the degeneration of dopaminergic neurons in old age?
Foxa2
Describe the effect of Engrailed deficiency on mice
Engrailed deficient mice develop dopaminergic neurons, but lose these neurons within 48 hours
Name the Engrailed subgroup of mice which gradually lose their dopaminergic neurons in the substantia nigra only
En1+/- ; En2-/-
What is the effect of engineering substantia nigra pars compacta neurons to expressed ventral tegmental area specific genes?
It is protective against pathology, suggesting that pro-survival genes are downregulated by the substantia nigra, leaving it inherently vulnerable
Describe the changes to alpha-synuclein in Lewy bodies
The alpha-synuclein is hyperphosphorylated, ubiquitinated, and aggregated, making it insoluble
Give at least 3 factors which increase the likelihood of alpha-synuclein aggregation
Genetic mutations, proteasome dysfunction, mitochondrial dysfunction, oxidative stress, phosphorylation
What is parkin?
An E3 ligase which participates in the addition of ubiquitin molecules to target proteins, marking them for degradation
What is the consequence of a loss of parkin function?
An inability to break down ageing or damaged proteins and organelles
Do parkin mutations cause autosomal dominant or recessive familial PD?
Recessive
Do PTEN-induced putative kinase 1 (PINK-1) mutations cause autosomal dominant or recessive familial PD?
Recessive
Give 2 functions of DJ1
1) Inhibiting the aggregation of alpha-synuclein via chaperone activity, protecting the cell from oxidative stress
2) Modulating the mitochondrial membrane potential
State the inheritance pattern of familial PD caused by mutated DJ1
Autosomal recessive
How is PD caused by a DJ1 mutation distinguished from PD caused by PINK-1 or parkin mutations?
It is early-onset
What is the consequence of PTEN-induced putative kinase 1 (PTEN-1) knockout in Drosophila?
Mitochondrial dysfunction, reduced respiratory chain activity, reduced ATP content of tissues, and increased propensity to apoptosis
