synucleopathies Flashcards
what is synucleopathies
Synucleinopathies are a group of neurodegenerative disorders in which the protein alpha-synuclein accumulates abnormally to form inclusions in the cell bodies or axons of neurons or oligodendrocytes.
what is the most common synucleopathy
Parkinson’s disease (PD)
which primary brain area do synucleopaties affect
Neuron loss and gliosis mainly in substantia nigra
this is the Dopaminergic pathway to basal ganglia: Movement control
How is the substantia nigra affected
there is a loss of melanin containing dopaminergic neurons. (melanin = pigment)
this leads to nigrostriatal dysfunction –> affects the basal ganglia
why is the function of the basal ganglia important
The “basal ganglia” refers to a group of subcortical nuclei responsible primarily for motor control, as well as other roles such as motor learning, executive functions and behaviors, and emotions.
which misbalance occurs in PD
dopamine decrease and acetylcholine increase
how do you diagnose PD
with a SPECT tracer (detects dopamine transporters in the brain)
–> further visualise with PET scan
State the progression of PD
- starts in the brain stem/olfactory bulb
2. spreads out to cortical areas
Define the PD pathology
caused by Lewy bodies (aggregates of a-synuclein oligomers)
loss of synapses
loss of neuronal function
what is a-synuclein
small synaptic protein, which plays a role in synaptic vesicle function.
loss of function results in decrease neurotransmitter release (dopamine decrease)
what are the toxic function and loss of function of a-syn oligomers
loss of function:
- disruption axonal transport
- mitochondrial dysfunction
- synaptic dysfunction
- inhibition ubiquitin/proteasome system (leads to even more oligomers)
toxic function
- oligomers
- ROS production
define the aggregation cascade in PD
monomers - oligomers - fibrils - Lewy bodies
what did electron microscopy find in PD patient
Lewy bodies are ubiquitin positive (cause of consequence?)
what are the 4 central themes in PD
- ROS
- UPS (ubiquitin-proteasome-system)
- mitochondria
- a-synuclein aggregation
what is the difference between PD and Parkinsonism
Parkinsonism doesn’t have Lewy bodies. ( a-synuclein doesn’t play a role)
how are microglia activated in PD
neuroinflammation is triggered by neuromelanin. Neuromelanin is released once the neuron dies, which triggers inflammatory responses (microglia)
Microglia cells activate the production of toxic cytokines which stimulate the degeneration of dopaminergic neurones even further
can PD lead to dementia (PDD)
yes, of the damage spreads out to cortisol area’s this can affect memory
Explain dementia with Lewy bodies (DLB)
This is a case of isolated dementia. The a-synuclein inclusions affect the brain, but not the substantia nigra. This is only found sporadically, not genetic. (Parkinsonism)
what is the distinction between Parkinsonism, PD, PDD and LBD
Parkinsonism: Lewy bodies
PD : a-synucleopathies, Lewy bodies restricted to the brainstem and limbic regions
PDD : a-synucleopathies, Lewy bodies extends to the neocortex
DLB: Lewy bodies extends to the neocortex
what are different treatments for PD
L-dopa: It is a precursor of dopamine which can enter the BBB
what is the Hydrophobic aggregation core
NAC domain
which mutation can stimulate altered/accumulate a-synuclein function
SNCA mutation
which mutations cause UPS dysfunction
UCHL, PARK2, DJ1
what induces Parkinsonism
MPTP, it affects the mitochondria
