Neurology 18: Movement Disorders 1 and 2 Flashcards
Describe the protein folding and what happens when it goes wrong.
Who kills them?
Proteins fold due to non-covalent bonds between amino acids
- Recall the ubiquitin proteasome system (UPS)-attaches to wrong folded proteins and makes them target for lysis
- If we get a protein that doesn’t fold correctly, it starts to aggregate with other wrong proteins
Abnormal proteins
3
Why do they become abnormal and whats some reasons why they wouldnt be destroyed when they should be?
Abnormal proteins:
- conformation abnormalities
- oxidative stress
- gene mutations
- cellular damage
Failure of the UPS system:
- E1 Ubiquitin activating enzyme
- E2: Ubiquitin conjugating enzyme
- E3: Responsible for specific protein targeting.
What is the Aetiology of Parkinons Disease?
6
- Only 3% cases are likely inherited
- Mutations in the a-synuclein , parkin (DJ-1 and LRRK2 genes
- Exposure to exogenous neurotoxins (herbicides, pesticides)
- head trauma
- most cases are idiopathic
Pathophysiology of Parkinsons
- Chaperone, UPS and Lysosomal failure
- Aggregations of alpha-synuclein and ubiquitin
- ER stress, and mitochondrial dysfunction
- Degeneration of dopaminergic neurone in the SNc
Why do we know it has to do with the dopaminergic cells?
-Dopamine synthesis results in the production of reactive oxygen species
! SNc dopaminergic cells have high levels of the neuromelanin - source of Fe2+ which may cause oxidative stress
! There is a tendency for alpha-synuclein to be expressed in melatonin containing dopaminergic cells
! High presence of the dopamine transporter (DAT) that pumps 1-methyl-4-phenylpyridinium ion (MPP) and perhaps other neurotoxins into the cell
Check out the graph on slide 9 and tell me about it and how dopamine affects the pathways?
-Getting rid of dopamine transmission to indirect pathways so we are unable to inhibit this pathway- so unable to move.
Regardless of whether we are unable to stimulate the direct pathway or inhibit the indirect pathway the result is the same- we are unable to move.
What are the signs and symptoms of Parkinsons Disease?
Look for meaning of each on slide 10
Bradykinesia / Akinesia ! Resting tremor ! Muscular rigidity • (cogwheel rigidity) ! Postural instability ! Loss of postural reflexes ! Freezing ! Turning “en bloc” ! Reduction of arm swing ! Shuffling (festinating) gait ! Difficulty initiating movement ! Dystonia ! Myerson glabellar sign ! Depression ! Hypophonia ! Hypomimia (what’s this?!) ! Micrographia (what’s this?!) T: Tremor R: Rigidity A: Akinesia P: Postural instability
Is there any lab or genetic testing for Parkinsons?
11
No, but can tell if they response to medication or have a history of a stroke, space occupying lesions, MRI shows?
What are the treatments out there for parkinsons
11
also why not just administer dopamine?
Levadopa (L-dopa) is the gold standard–> pre-cursor to dopamine. Side effects- body then relies on it more so when they run out they just freeze.
-Decarboxylase inhibitor?
-Anticholinergic agents
-Stereotactic neurosurgery
-deep brain stimulation
Others: Physical therapy, exercise, psychological support.
Dopamine can’t cross the blood brain barrier but Levadopa (pre-cursor) does
What is Huntingtons Disease?
12
Huntington’s disease is a neurological (nervous system) condition caused by an altered gene. The death of brain cells in certain areas of the brain results in gradual loss of cognitive (thinking), physical and emotional function.
- triad of autosomal dominate inheritance, choreoathetosis and dementia
- symptoms begin 30-40’s
What is the pathogenesis and pathophysiology of hunting tons?
- aggregation of mutant huntington proteins - trinucleotide CAG repeats. Normal <35
- degeneration of enkephalinergic striatopallidal neurons in the neostriatum -indirect pathway coz their enkephalinergic
- Results in dysfunction of indirect loop
- leads to hyperkinesia
- median duration of disease is approx 20yrs
view table on slide 13
what are the signs and symptoms of Huntingtons disease on slide 14
reasons for each refer to slide 14
Choreoathetosis ! Dystonia Restlessness Cognitive decline ! Dementia Irritability Weight loss ! Dysphagia
What is the treatment for huntingtons?
Symptomatic only (at present) ! Pharmacological • Dopamine antagonists • Antipsychotic agents ! Genetic counseling of relatives ! Physical therapies ! Speech therapist (for ?) ! Psychological therapies
Basal Ganglia: Clinical correlations Hemiballism
15
Due to a lesion in the subthalamic nucleus (usually a result of a ?)
! Removes stimulation of the GPi
! GPi is unable to inhibit the thalamus
! Disinhibition of the thalamus leads to hyperkinesis
! Large, flinging rotatory movements of the limbs
What is dystonia
slide 17
In which sustained muscle contractions cause twisting and repetitive movements or abnormal postures.
- involuntary muscular contractions
- twisting, repetitive movements leading to abnormal posturing
- characteristically present during attempted voluntary movements
- Primary vs Secondary
- Pathogenesis is failure of one of the circuites in the indirect loop.
