17Neuro - Parkinson's Disease Flashcards
(32 cards)
Who was the first person to describe Parkinson’s Disease?
James Parkinson in 1817.
What is Parkinson’s disease?
A movement disorder characterised by:
Bradykinesia (slowness), akinesia (absence of movement), muscle stiffness, tremor of limbs = typically in hands, postural instability
Progressive degeneration of CNS, increasing incidence with age, 1% of those over 55
What forms of Parkinson’s disease exist?
Sporadic - 90% (mostly idiopathic - unknown causes)
Drug-induced (rare - from the 1980s)
Familial (10-15%)
What are the main pathological features of Parkinson’s disease?
Loss of pigmented neurons (neuromelanin granules) of substantia nigra = black substance
Appearance of intracellular accumulations of insoluble proteins
LEWY BODIES, in the substantia nigra, which contain ubiquitin, α-synuclein and neurofilament proteins
Describe some of the neurochemistry involved in Parkinson’s disease.
Reserpine which lowers monoamine levels, results in Parkinsonism = Used to treat hypertension
L-dopa alleviated reserpine-induced symptoms = A precursor of dopamine
Dopamine levels reduced in basal ganglia of Parkinsonism patients
Associated with loss of 80% of substantia nigra neurons = to produce symptoms
How is the substantia nigra linked to movement disorders?
Substantia nigra neurons release dopamine in basal ganglia (which regulates movement)
Movement problems result of dopamine deficit
Neurons of substantia nigra have long processed which reach the basal ganglia = regulation of movement disregulated in Parkinson’s disease
What is the substantia nigra pars compacta?
SNpc = Substantia Nigra pars compacta = portion of the substantia nigra formed by dopaminergic nerves = loss of substantia nigra neurons decreases capacity of the nigrostriatal pathway
How can PET be used in the diagnosis of Parkinson’s disease?
Positron Emission Tomography showing caudate and putamen
Dopaminergic nerves release dopamine but will also reuptake dopamine via a reuptake transporter mechanism to control [neurotransmitter] in synapse
A radioactive ligand can be used to visualise dopamine reuptake
How is dopamine metabolism in the substantia nigra linked to neurodegeneration in Parkinson’s disease?
Neurons of substantia nigra produce and release dopamine
Degradation of dopamine yields H2O2 and superoxide ion
H2O2 could react with Fe2+ to yield •HO
Death of SN neurons could lead to increased dopamine turnover in surviving neurons and increased ROS
Feed forward = once cells start to die, the remaining cells die at an accelerated rate
Cells of the substantia nigra are at particular risk due to their role in dopamine release
How is dopamine broken down?
Dopamine can be broken down enzymatically or non-enzymatically.
The enzymatic route sees dopamine plus water being converted to 3,4-dihydroxyphenylacetaldehyde, hydrogen peroxide and ammonia by the enzyme MAO B.
The non-enzymatic route sees dopamine and oxygen being converted to semiquinone, superoxide and a proton.
Dopamine can also combine with superoxide and 2 protons to form semiquinone and hydrogen peroxide.
Why can dopamine be broken down by MAO B?
Dopamine is a monoamine it can therefore be degraded by Monoamine oxidase B (MAO B)
What is a hallmark of most cases of Parkinson’s disease?
Hallmark of most cases of Parkinson’s Disease is protein inclusion bodies in the cytoplasm (Lewy bodies) and nerve fibres (Lewy neurites)
Contain α-synuclein, which may be nitrated (free-radical damage) and abnormally glycosylated
Ubiquitin and components of ubiquitin-proteasome system and hsp70 chaperone = may be a failed attempt to remove
Lewy bodies may be aggresomes = cytoprotective inclusions which slowly deliver misfolded proteins to autophagy (autophagy = lysosomal system for degradation)
What caused drug-induced Parkinsonism in the 1970s?
In 1978, Californian drug addict synthesised “false heroin” to evade drug laws
Users developed symptoms associated with Parkinson’s Disease
By-product of synthesis is a pyridine, 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP)
MPTP metabolised to toxic MPP+ (1-methyl-4-phenylpyridinium) by astrocytes
MPP+ taken up by dopamine reuptake system (DAT) which may provide selectivity for dopaminergic neurons
MPP+ binds non-covalently to ubiquinone of NADH-dehydrogenase complex
Blocks electron transport due to free radicals formed from MPP+ (?)
Blocked electron transport may release electrons which will reduce oxygen to superoxide
Loss of mitochondrial membrane potential may lead to apoptosis - release of cytochrome c
Toxicity of MPP+ in vitro depends on nitric oxide synthase (NOS) activity - possible reactive nitrogen species (RNS) involvement
Mitochondrial damage = ROS/RNS = apoptosis
How are free radicals linked to Parkinson’s disease?
Tissue from sporadic Parkinson’s disease exhibit lower activity of mitochondrial complex I
Lower levels of glutathione (GSH) in the substantia nigra = suggesting free radical exposure as glutathione is an anti-oxidant
Increased levels of iron = Fenton reaction
With no concomitant increase in transferrin
Fe2+ levels high in the neuromelanin in the substantia nigra (normal brain)
High ROS, Fe2+ leads to •OH
What mutations have been identified in familial Parkinson’s disease?
Familial cases of Parkinson’s disease identified with a mutation in α-synuclein (PARK1)
A53T, A30P, G46K autosomal dominant
Toxic gain of function?
Gene duplication and triplication causes Parkinson’s disease
Gene dosage effect? = something intrinsic of alpha-synuclein
Mutant synuclein forms pleated-sheet like structure and aggregates
Non-amyloid component (NAC) domain promotes aggregation
Non-PD “synucleinopathies” e.g. Diffuse Lewy Body Disease = affects different neurons = cerebral cortex = leads to cognition problems = form of dementia
What feature of alpha-synuclein makes it prone to aggregation?
IDP = intrinsically disordered protein
Structure of protein changes readily can easily form toxic aggregates
Describe some of the main features of alpha-synuclein.
Largely unstructured (Intrinsically Disordered Protein, IDP) forms amino-terminal α-helices on binding acidic phospholipids Binds neurotransmitter vesicles (dopamine containing), possible chaperone Possible modulator of VMAT2 - dopamine transporter VMAT2 takes up cytosolic dopamine into vesicles
How is alpha-synuclein linked to fibril formation?
α-synuclein readily forms β-sheet-like structure (normal structure is more alpha-helical) leading to fibril formation resulting from:
Mutations associated with Parkinson’s disease (e.g. A53T)
Gene duplication - over expression
Free radical damage e.g. tyrosine nitration
Synuclein aggregation impairs ubiquitin-proteasome system = leads to synuclein accumulation and more oligomerization/fibrils
Reduction in UPS activity leads to Lewy Body formation (aggresome?)
How is alpha-synuclein linked to Parkinson’s disease pathology?
α-synuclein (soluble) oligomers:
Form Ca2+ pores in the cell membrane = free radical production = toxic effects
Bind to mitochondria = electron leakage, ROS formation
Disrupt vesicle trafficking/dopamine transport = increase in dopamine metabolism = ROS
Disrupt the cytoskeleton = Large aggegates
May start in the gut and travel up nerves to the brain, and pass from cell to cell - prion-like = Protein conformation transmitted
A mutation in which gene leads to autosomal recessive juvenile onset Parkinson’s disease?
An Autosomal Recessive - Juvenile Parkinsonism (AR-JP) results from mutations in the Parkin (PARK2) on chromosome 6
AR-JP onset in early 30s
Loss of cells in substantia nigra, tyrosine hydroxylase (catecholamine biosynthesis) activity low
How is ARJP different to other forms of Parkinson’s disease?
No inclusion bodies (LB) detectable with antibodies to α-synuclein or ubiquitin - Parkin required?
What is Parkin? Describe its main features.
Parkin
One of largest human genes, over 1Mb, 12 exons coding for 465-residue 52kDa protein
Cytosolic E3 ubiquitin-ligase
N-terminal 76-amino acids similar to ubiquitin
Central unique “Parkin” domain
C-terminal RING finger - IBR (In Between Ring finger domain) - RING finger
C-terminal portion (PAUL) similar to “ariadne” ubiquitin ligases
Abundant in substantia nigra
Multi-domain protein
How are mutations in PINK1 and DJ-1 linked to familial Parkinson’s disease?
Mutations in PINK1 (PARK6) and DJ-1 (PARK7) lead to autosomal early onset PD
PINK1 (PTEN): mitochondrial kinase involved in stress response - mitochondrial fission?
DJ-1: involved in stress response, translocates to mitochondria following oxidative stress - promotes mitochondrial fission?
How are PINK1 and Parkin related to mitophagy?
PINK1 associates with mitochondria when mitochondria de-polarised
Otherwise, cleaved and fragment in cytosol associated with Parkin = doesn’t occur when damaged
DJ-1 recruited to outer mitochondrial membrane when mitochondria
PINK1, DJ-1 and Parkin form (soluble) complex
Defective mitochondria accumulate in Parkin, Pink1 Drosophila mutants
Uncoupled mitochondria:
Identified by Pink1, ubiquitylation by Parkin (K63)?, mitochondrion degraded by autophagy (mitophagy) and OMM by proteasome
Parkin/PINK1/DJ-1 (?) necessary for elimination of damaged mitochondria?
Loss of function leads to accumulation of damaged mitochondria triggering apoptosis?
Formation of phagopore in cytoplasm surrounds mitochondria = degraded
