Genetics and Epigenetics of Parkinson's Disease Flashcards
Name the principle gene mutations associated with the familial forms of Parkinson's disease and describe the cellular functions of the proteins which these genes encode for Describe the neurodegenerative pathways associated with these mutated proteins and discuss whether neurodegeneration pathways for the familial and sporadic forms of PD overlap Discuss how genome-wide association studies have identified risk genes for the development of idiopathic PD and how they have been used to identify key
Which gene is mutated to cause Perry syndrome?
DCTN1
What is Perry syndrome?
A progressive brain disease characterised by 4 main features: parkinsonism, psychiatric changes, weight loss, and hypoventilation. It is typically diagnosed between 35-61, and average survival after diagnosis is 5 years
Other than the brain, where is alpha-synuclein found?
Heart, muscles, and blood
What is the locus of the parkin gene?
PARK2
What is the locus of the PINK1 gene?
PARK6
Why is systemic alpha-synuclein inhibition not a therapeutic option in PD?
It could affect the maturation of red blood cells
What functions is alpha-synuclein believed to be involved in?
Synaptic vesicular trafficking (by promoting membrane curvature), SNARE complex assembly, neurotransmitter release
What is leucine-rich repeat kinase 2 (LRRK2) and where is it found?
A mixed lineage-like kinase found in the cytoplasm and outer membrane of mitochondria
What do LRRK2 mutations cause?
Apoptotic cell death
What is the most common cause of familial PD?
LRRK2 mutations
Do LRRK2 mutations guarantee the development of PD?
No
Which other protein implicated in familial PD does LRRK2 interact with?
Parkin
What is parkin and what is its function?
A ubiquitin E3 ligase linked to the regulation of apoptosis and the turnover of damaged mitochondria
How does PTEN-induced putative kinase 1 (PINK1) induce mitochondrial autophagy?
It causes parkin to bind to depolarised mitochondria
Which protein family is DJ1 part of?
C56 peptidase family
What are the functions of DJ1?
It is a redox-sensitive chaperone that functions as a sensor for oxidative stress and stabilises the mitochondrial membrane potential
Are LRRK2 mutations autosomal dominant or recessive?
Dominant
What is the locus of the LRRK2 gene?
PARK8
How many mutations causing familial PD have been identified on the alpha-synuclein gene?
3
How does faulty alpha-synuclein lead to free radical formation and cell damage?
Alpha-synuclein is involved in SNARE complex formation, so faulty alpha-synuclein impairs the release of neurotransmitters. This leads to dopamine leaking out of vesicles, causing free radical formation and cell damage
What form is alpha-synuclein in in healthy individuals?
Either a monomer or a flexible tetramer, in a dynamic equilibrium
In which form does alpha-synuclein perform its usual functions?
Flexible tetramer
State at least 4 pathological roles of misfolded alpha-synuclein
Lewy body formation and propagation, inhibition of autophagy, complex I inhibition (leading to mitochondrial fission and free radical formation), proteasome inhibition
Why might alpha-synuclein oligomers be more damaging than Lewy bodies?
Oligomeric alpha-synuclein interferes with proteasome function (allowing toxic aggregates to remain), inhibits complex I (starving the cell of energy and producing free radicals), and interacts with the mitochondrial transition pore (causing it to become more leaky and triggering apoptosis)
Describe evidence against PD pathology starting in the gut and travelling to the brain via the enteric nervous system and vagus nerve
25% of PD patients have no pathology in the dorsal motor nucleus of vagus
Name the areas involved in Braak stages 1 and 2
Dorsal motor nucleus of vagus, anterior olfactory bulb, raphe nucleus, locus coeruleus
Name the additional area involved in Braak stage 3
Substantia nigra pars compacta
Name the additional areas involved in Braak stage 4
Amygdala, nucleus basalis of Mynert, hippocampus
Who identified LRRK2 mutations in familial PD and when?
Funayama M et al in 2002
What is the most frequent LRRK2 mutation?
G2019S
Name 2 other diseases associated with LRRK2 mutations
Progressive supranuclear palsy (PSP) and multiple system atrophy (MSA)
How much do glucocerebrosidase (GBA) mutations increase susceptibility to PD?
20%
In which population are glucocerebrosidase (GBA) mutations most common?
Ashkenazi Jews
What disease is caused by mutations in glucocerebrosidase (GBA)?
Gaucher disease - a lysosomal storage disease
State at least 3 symptoms of Gaucher disease
Anaemia, fatigue (reduced haemoglobin), bleeding, bruising (reduced platelets), dyspnoea (reduced lung function), abdominal distension (hepatomegaly and splenomegaly), bone pain, fractures (reduced bone density)
Name a risk gene for PD identified by GWAS
Microtubule-associated protein tau (MAPT), bone marrow stromal cell antigen 1 (BST1), cyclin-G-associated kinase (GAK)
Define epigenetics
The process by which DNA is altered without altering the genetic code
State 2 epigenetic mechanisms
DNA methylation and histone modification
Describe epigenetic DNA methylation
Gene repression through the physical blocking of DNA to transcription factors (repulsion) and recruitment of methyl binding proteins to exacerbate the blockade
Describe epigenetic histone modification
The use of HDACs to make the chromatin packaging of histones more condensed, and hence transcriptionally inactive, and the use of HATs to add acetyl groups and push histones apart to permit gene transcription
How does PD cause hypomethylation?
The DNA methyltransferase DNMT1 is translocated out of the nucleus
How does PD affect histone modification?
Alpha-synuclein accumulation promotes histone H3 hypoacetylation and masks histone H3
Describe the result of mouse trials into the use of valproate in inhibit HDACs and improve PD symptoms
The mice had improved motor symptoms and reversed cell loss
