Case 7 - Parkinson's Pathophysiology Flashcards
where does PD firstly affect the brain
firstly affects the dorsal motor nucleus of the vagus nerve and the olfactory bulbs and nucleus
where does it affect after this
the locus coerleus
then eventually the substantia nigra
cortical areas of the brain are affected at a later stage
what happens to unused dopamine
is absorbed back into the presynaptic cell, once back in the cell, the excess dopamine is repackage into storage vesicles and released once more into the synapse
what two enzymes break down dopamine
MAO - monoamine oxidasse
COMT - catechol-0-methyl transferase
where is degeneration of dopamine neurones particularly evident
in a part of the substantia nigra called the pars compacta
what does the loss of dopamine in the pars compacta do
increases the overall excitatory drive of the basal ganglia, disrupting voluntary motor control and causing the characteristic symptoms of PD
what are Lewy bodies
are abnormal aggregates and inclusions of protein that develop inside nerve cells of people who have Parkinson’s
what do the aggregations consist of
insoluble fibrillary aggregates containing misfolded proteins
what is the main component of Lewy bodies
alpha synuclein
what do these inclusions and aggregates likely symbolise
the end stage of a cascade of complicated events. an earlier stage may be more directly tied up to the pathogenesis of the disorder than the inclusions themselves, which may or may not represent diagnostic hallmarks
what is Parkinsonism
a neurologic syndrome in which a patient exhibits dome of the symptoms associated with Parkinson’s disease, tremor, rigidity, bradykinesia and postural instability
are Lewy bodies seen in Parkinsonism
no
what is the largest nucleus of the basal ganglia
the striatum which consists of the caudate nucleus and the putamen
what does the SNCA gene do
encodes the protein alpha-synuclein, the main components of Lewy bodies and the noted pathology marks in autopsy slides of PD brains
what do mutations in the SNCA gene account for
about 2% of the familial cases, though not all persons with these changes have development PD
how is SNCA transmitted
in a dominant fashion
what does alpha synuclein also do
regulates the release of neurotransmitters at the presynaptic terminal. in addition, it seems to modulate intracellular dopamine concentration through interactions with proteins that regulate dopamine synthesis and uptake
what is the PARK8 (LRRK2) gene
is a signalling protein that becomes toxic when it mutates
what does the LRRK2 gene encode for
protein called dardarin
what is the dardarin protein
one segment of the protein contains a large amount of an amino acid called leucine.
what to proteins with leucine rich regions appear to do
play a role in activities that require interactions with other proteins such as transmitting signals or helping to assemble the cells structural cytoskeleton
what are the recessive genes in PD
PARK2
PARK6 - PINK1
DJ-1 - PARK7
what is the PARK2 - PARKIN gene
one of the largest human genes, provides instructions for making a protein called Parkin which plays a role in the breakdown of unneeded proteins
how does it break down unneeded proteins
by tagging damaged and excess proteins with molecules called ubiquitin.
what does ubiquitin serve as
a signal to move unneeded proteins into specialised cell structures known as proteasome, where the proteins are degraded
what does the ubiquitin-proteasome system act as
the cells’ quality control by disposing of damaged, misshapen and excess proteins.
this system also regulates the availability of proteins that are involved in several critical cell activites, such as the timing of cell divisions and growth. because of its activity in the ubiquitin-proteasome system,Parkin belongs to a group of proteins
what is the group of proteins that Parkin belongs to called
E3 ubiquitin ligases
what else is Parkin involved in
the maintenance of mitochondria, the energy producing centres in cells
what does PINK1 do
senses damaged mitochondria and recruits and activates Parkin to degrade and recycle damaged mitochondria.
where are the loss of neurones in PD
the nigrostriatal dopaminergic neurones
what happens when the compacta cells are destroyed in PD
the inhibitory outflow of the basal ganglia is abnormally high, and thalamic activation of upper motor neurones in the motor cortex is therefore less likely to occur
what happens to the D1 receptors in PD
less activation - means that there will be a decrease in dynorphin, thus causing a decrease in the stimulation of the direct pathway
what happens to the D2 receptor In PD
less activation which means there will be an increase in enkephalin, thus causing a decrease in the inhibition in the indirect pathway
what do surviving neurones contain
aggregations of protein called Lewy bodies
