lecture 19 Flashcards
neurodegeneration module - how would you do research on causes of neurodegeneration?
What is the impact of diseases of the brain?
- extremely burdensome on society
- major public health problem
What is the classic approach to making a model?
- e.g. introduce a pathogen into mouse
a model:
- explain pathogenesis
- histology
- biochemistry
- phenotype
- is this kind of model appropriate when studying neurodegeneration?
What ‘isn’t’ neurodegeneration?
- single cause/entity e.g. virus
- if you remove pathogen you can remove disease
- degenerative diseases are different
What happens when we investigate a disease in an individual?
- we have to follow the reverse path of degeneration
- failed organ –> active disease –> disease onset –> risk factors
“Dropsy”
heart failure
caused by Heart Attacl, muscle disease, valve disease
caused by atheroma, clotting disorder, embolus, infection
brought about by risk factors e.g. hypertension, diabetes, smoking, lipid disorders, genetics
What has been the history of investigation into Parkinson’s disease?
first described as Shaking Palsy
- described by James Parkinson in 1817
- Paralysis Agitans
- involuntary tremulous motion
- lessened muscular power
- in parts not in action and even when supported
- with a propensity to bend the trunk forward and to pass from a walking to a running pace: the sense and intellect being uninjured
1895: E. Brissaud found that substantia nigra cell loss was seen in patients with the disease
- 50-70% are lost when symptoms start
- normal subject has the black substance (Substantia Nigra)
1912: F. H. Lewy found Lewy Bodies
- pathological marker within the brain of people with parkinson’s
1960s: Dahlstron, Fuxe & Hornykiewicz
- Dopamine and its use in Parkinson’s disease
- L-Dopa (L-AAAD) –> Dopamine
1997 Polymeropoulos et a.
- α-synuclein mutation in a Greek family with autosomal dominant Parkinson’s
1998 Spillantini et al, Baba M et al
- α-synuclein the primary component of Lewy bodies
What is a simple model of Parkinson’s disease? (in reverse order)
- Failed organ: motor symptoms of PD
- Active disease: loss of Mid Brain neurones causing loss of Dopamine transmission
- disturbance in α-synuclein causing Lewy bodies
- Risk factors ? + genes
Why does clinical examination matter?
- because we are working backwards from failed organ to risk factors
> clinical signs “phenotype”
> brain region injured
> regional function due to 1. cell type, 2. circuitry
> cell type due to gene expression, 1. biochemistry, 2. cell morphology, 3. energy demands
What is an example of the importance of clinical examination?
Amyotrophic Sclerosis, Motor Neuron Disease
- weakness/paralyses, increased reflexes
> Upper Motor Neurons
- increased reflexes
- weakness/paralyses
- loss of reflexes, fasciculation > lower motor neurones - wasting - weakness/paralyses - fasciculations
- no sensory features
similar neurones - common embryology - long axons (high energy needs) - same transmitters - similar morphology - similar gene expression = similar risk to MND
mutations in the gene for SOD1 are associated with familial MND
- the chesapeake retriever breed has mutations in SOD1
- but the dog has pathology in sensory spinal neurones - not motor neurones
- what is the different gene expression between human and dog sensory neurons?
- this would point to key permitting/inhibiting mechanisms
What are the clinical signs of late PD?
- motor signs (at disease onset > failed organ)
- sleep disorder - pre-symptom, risk factors?
- autonomic failure - pre-symptom, risk factors?
- dementia: active disease, maybe as early as pre-symptom
- impulsivity: active disease
- neuro-psychiatry: active disease/failed organ
two possibilities:
- they occur sequentially: cascade, spreading and affecting different regions
- OR the disease all happens at once but different cells are more susceptible than others
How can the presence of Lewy Bodies help reveal the progression of Parkinson’s
- Lewy bodies first seen in neurons in the gut/spinal cord - seen in every person with Parkinson’s, early Parkinson’s etc
- next seen in the brain stem in the region that controls sleep
- third found in motor regions that control substantia nigra
- thalamus
- cortex
- lastly in the regions that control hallucinations/impulsivity
- this gives the idea that the disease is spreading up the CNS rather than susceptibility
What are conclusions and questions RE: Parkinson’s?
- PD is more than Motor Symptoms
- other disease can cause similar Motor Symptoms (now called parkinsonism) to distinguish from PD
- Are there similar neurone types/processes to explain all features of PD?
- why do neurodegenerations spread? is it that some cells are less susceptible? is it an “infection”?
What protein abnormalities are associated with different neurodegenerations?
- Alzheimer’s - Aβ
- Parkinson’s - α-synuclein
- Dementia with Lewy Bodies - α-synuclein
- Progressive Supranuclear Palsy and Basal Ganglionic Degeneration - Tau
- Fronto-Temporal dementia - Tau and TDP43
- MND - TDP43, FUS, SOD1 etc
- CJD - Prion protein
Can you use the protein to diagnose the disease?
not necessarily, while it may be a key player it is becoming apparent that there is quite a bit of overlap
it’s not quite so clear cut
What do we mean by the term neurodegeneration?
progressive death of neurones: usually specific subsets
the idea of progression is key to the idea of degeneration
it is not an acute/static injury
How does neural capacity progress? How is this significant?
- an infant has a limited repertoire of neural capacity available to it
- quickly develops
- full repertoire of behaviour usually comes at about 20
- (in the male propositional thought doesn’t develop ever in about 20% of individuals…)
- if you had an injury in a child you would expect them to continue to develop - set back
- injury at 40 - lowered but stable after that
- as you get older capacity remains stable, doesn’t fall off
- there isn’t necessarily a process of just ‘getting old’
- diseases are what cause the neurodegeneration
- child with a neurodegeneration (particularly under the age of 10) will slowly lose the neural capacity that they gained: progressively worse instead of slowly better
- severe genetic abnormalities
- young onset may not reach full capacity… degeneration
- Less severe genetic abnormalities or increased expression of late onset genes
late onset: slower decline
- post fertile genes advantageous?
- mechanisms common to all neurodegeneration ?
- failing energetics
- neurones do not replicate
