Parkinson’s disease.
Parkinson’s disease is the second most common neurodegenerative disorder after
Alzheimer’s.
1% of the population over the age of 60 and 4% of the population over the age of 80.
The primary hallmarks:
Loss of dopaminergic neurons in the substantia nigra pars compacta of the midbrain.
Cytoplasmic and axonal accumulation of alpha-synuclein in Lewy bodies, if they are
localised in the soma of the cells or Lewy neurites if they are localised in the axon.
Symptoms:
4 clinical motor symptoms: resting tremor, bradykinesia, rigidity, and gait
impairment.
Additional clinical symptoms: autonomic dysfunction, psychiatric disorders, sleep
disorders and olfactory dysfunction.
PD neurological aspects: why does the loss of DN in PD cause motor symptoms:
There is a loss of neurones in the substantia nigra.
The basal ganglia are deep nuclei that play a key role in the regulation of motor
function. The help regulate our motor response.
Basal ganglia are 3 structures: the first nucleus is called caudate nucleus, then
there is the putamen, then there is the globus pallidus.
The caudate and putamen together is the striatum, and this is because in a
histological section this region appears as striated.
In PD the basal ganglia are impaired.
The primary function of the basal ganglia is to provide a feedback mechanism to
the cortex for the initiation and control of motor responses.
The thalamus is the most important relay station for all the outputs to the
cerebral cortex, the thalamus always wants to excite the cortex.
The function of the basal ganglia is to modulate the thalamus output to the
cerebral cortex. The basal ganglia do this via the striatum, so basal ganglia
influences neurones in the thalamus via two different pathways that are called
the direct and indirect pathways.
These two pathways are modulated by dopamine which is produced by the
substantia Niagara dopaminergic neurones.
In normal conditions:
The substantia nigra neurones project to the striatum, and the striatum projects
to the thalamus to the cortex. And the final result is the normal control of motor
activity.
In Parkinson’s disease case:
There is much less dopamine or no dopamine, so there is no modulation of
output from the basal ganglia to the thalamus. The final result is an altered
motor output of the cortex.
So in a normal role dopamine has to facilitate the activity in the motor areas of
the cerebral cortex.
, In Parkinson’s disease there is no dopamine, the dopaminergic neurones die, and
the final result is an altered motor output of the cerebral cortex.
Sporadic VS familial PD.
Sporadic means that we don’t know why these people develop Parkinson’s disease.
This is 90% of all patients.
the major risk for developing sporadic PD is age. Average age that PD is diagnosed is
60 years.
There is usually a slow progression.
There are some environmental factors which can increase the risk of developing
sporadic PD. Such as exposure to pesticides.
Genetic cases: these people develop PD because they have a mutation in a very
specific gene.
This affects 5-10% of all patients.
These patients are affected at an earlier age <50 years.
The disease in these patients is more severe and generally progresses more quickly.
Although it is gene dependant.
Mutations in these genes cause PD: SNCA, LRRK2, parkin etc.
There are genetic factors, there are genetic variants that can increase the risk for
developing Parkinson’s disease.
There are environmental factors: exposure to pesticides, head injury etc.
There are also epigenetics: this is any factor that can influence gene expression, that
is not mediated by the DNA sequence itself.
The final result that takes into account genetic, environmental and epigenetic factors
can be not PD causative.
Heterogeneity in PD neuropathology: nigral neuronal loss in PD is NOT always
accompanied by the presence of Lewy bodies in the brain: LB are missing in a subset
of affected PINK1, parkin and LRRK2 mutation carriers.
These also may mean that there may be several different pathophysiological
pathways leading to the loss of dopamine signalling in the striatum.
Lewy bodies and alpha syn role in PD.
Lewy bodies are an accumulation of alpha synuclein.
Alpha-syn structure (14KDa).
There are 3 parts to the protein:
N terminal repeat region, NAC region, and a C-terminal.
N terminal region is important for membrane recognition. There is the presence of 7
similar domains, and they all contain motif KTKEGV. This motif is important for the
interaction with the membranes. This region enables alpha synuclein to act as a
secondary structure, the structure of an amphipathic alpha helix. An amphipathic
molecule has a polar part and a non-polar part, the presence of the N terminal
repeat region is what makes alpha synuclein able to acquire a secondary structure
of an amphipathic alpha helix. This can then interact with membranes, such as
synaptic vesicles and it is important for the ability of the alpha synuclein to disrupt
the membrane structure.
Parkinson’s disease is the second most common neurodegenerative disorder after
Alzheimer’s.
1% of the population over the age of 60 and 4% of the population over the age of 80.
The primary hallmarks:
Loss of dopaminergic neurons in the substantia nigra pars compacta of the midbrain.
Cytoplasmic and axonal accumulation of alpha-synuclein in Lewy bodies, if they are
localised in the soma of the cells or Lewy neurites if they are localised in the axon.
Symptoms:
4 clinical motor symptoms: resting tremor, bradykinesia, rigidity, and gait
impairment.
Additional clinical symptoms: autonomic dysfunction, psychiatric disorders, sleep
disorders and olfactory dysfunction.
PD neurological aspects: why does the loss of DN in PD cause motor symptoms:
There is a loss of neurones in the substantia nigra.
The basal ganglia are deep nuclei that play a key role in the regulation of motor
function. The help regulate our motor response.
Basal ganglia are 3 structures: the first nucleus is called caudate nucleus, then
there is the putamen, then there is the globus pallidus.
The caudate and putamen together is the striatum, and this is because in a
histological section this region appears as striated.
In PD the basal ganglia are impaired.
The primary function of the basal ganglia is to provide a feedback mechanism to
the cortex for the initiation and control of motor responses.
The thalamus is the most important relay station for all the outputs to the
cerebral cortex, the thalamus always wants to excite the cortex.
The function of the basal ganglia is to modulate the thalamus output to the
cerebral cortex. The basal ganglia do this via the striatum, so basal ganglia
influences neurones in the thalamus via two different pathways that are called
the direct and indirect pathways.
These two pathways are modulated by dopamine which is produced by the
substantia Niagara dopaminergic neurones.
In normal conditions:
The substantia nigra neurones project to the striatum, and the striatum projects
to the thalamus to the cortex. And the final result is the normal control of motor
activity.
In Parkinson’s disease case:
There is much less dopamine or no dopamine, so there is no modulation of
output from the basal ganglia to the thalamus. The final result is an altered
motor output of the cortex.
So in a normal role dopamine has to facilitate the activity in the motor areas of
the cerebral cortex.
, In Parkinson’s disease there is no dopamine, the dopaminergic neurones die, and
the final result is an altered motor output of the cerebral cortex.
Sporadic VS familial PD.
Sporadic means that we don’t know why these people develop Parkinson’s disease.
This is 90% of all patients.
the major risk for developing sporadic PD is age. Average age that PD is diagnosed is
60 years.
There is usually a slow progression.
There are some environmental factors which can increase the risk of developing
sporadic PD. Such as exposure to pesticides.
Genetic cases: these people develop PD because they have a mutation in a very
specific gene.
This affects 5-10% of all patients.
These patients are affected at an earlier age <50 years.
The disease in these patients is more severe and generally progresses more quickly.
Although it is gene dependant.
Mutations in these genes cause PD: SNCA, LRRK2, parkin etc.
There are genetic factors, there are genetic variants that can increase the risk for
developing Parkinson’s disease.
There are environmental factors: exposure to pesticides, head injury etc.
There are also epigenetics: this is any factor that can influence gene expression, that
is not mediated by the DNA sequence itself.
The final result that takes into account genetic, environmental and epigenetic factors
can be not PD causative.
Heterogeneity in PD neuropathology: nigral neuronal loss in PD is NOT always
accompanied by the presence of Lewy bodies in the brain: LB are missing in a subset
of affected PINK1, parkin and LRRK2 mutation carriers.
These also may mean that there may be several different pathophysiological
pathways leading to the loss of dopamine signalling in the striatum.
Lewy bodies and alpha syn role in PD.
Lewy bodies are an accumulation of alpha synuclein.
Alpha-syn structure (14KDa).
There are 3 parts to the protein:
N terminal repeat region, NAC region, and a C-terminal.
N terminal region is important for membrane recognition. There is the presence of 7
similar domains, and they all contain motif KTKEGV. This motif is important for the
interaction with the membranes. This region enables alpha synuclein to act as a
secondary structure, the structure of an amphipathic alpha helix. An amphipathic
molecule has a polar part and a non-polar part, the presence of the N terminal
repeat region is what makes alpha synuclein able to acquire a secondary structure
of an amphipathic alpha helix. This can then interact with membranes, such as
synaptic vesicles and it is important for the ability of the alpha synuclein to disrupt
the membrane structure.
