Neurodegenerative diseases Flashcards
1
Q
What is a neurodegenerative disease?
A
- incurable debilitating disease caused by the progressive loss of specific neuronal populations
- usually older onset
- lack of knowledge on the early stages of disease
2
Q
Why is the central nervous system susceptible to neurodegeneration?
A
- very few stem cells, cells cant regenerate after being lost
- hard to replicate such complexity
3
Q
Are there stem cells in the brain?
A
- very few
- limited to the dentate gyrus, subrentricular zone and the rostral migratory stream
- cells elsewhere cannot be replaced following damage and loss
4
Q
Name 4 common neurodegenerative diseases
A
- Alzheimer’s
- Huntington’s
- Parkinson’s
- Amyotrophic lateral sclerosis
5
Q
What are the clinical symptoms of Alzhimer’s and the typical age of onset?
A
- cognitive decline and memory loss
- inability to perform daily tasks
-confusion and aggression in some - typical age of onset is over 65
6
Q
What are the pathological features of Alzheimer’s?
A
-widespread atrophy
- build-up of B-amyloid leads to the formation of amyloid plaques
- accumulation of hyperphosphorylated tau protein in cell bodies and neurites leads to the formation of neurofibrillary tangles
7
Q
What causes Alzheimer’s?
A
- 1% are familial
- mutations in beta-secretase, x-secretase
- APP mutations and triplications (down syndrome)
8
Q
What are some risk factors for Alzhimer’s?
A
- age
- obesity
- ApoE4 allele
- high blood pressure
- other gene factors
9
Q
How are Tau neurofilaments produced in Alzheimer’s?
A
- inflammation and damage leads to hyperphosphorylation of tau protein
- causes microtubule instability
- tau is released from the microtubules and aggregates in the cell bodies and neurites
10
Q
What knowledge are we still missing for Alzheimer’s disease?
A
- early stages
- amyloid plaques are also seen in the brains of healthy older people
- what is the eitology? vascular, inflammatory, infectious?
- how are tau burden and cognitive decline linked
11
Q
What are the current methods/attempts to tackle Alzheimer’s?
A
- prevent accumulation of B-amyloid and amyloid plaques by modulating b-secretase
- prevent accumulation or increase clearance of Tau protein with GSK-inhibitors (bad side effects as GSK is a widespread kinase)
- life changes in diet and exercise
12
Q
What are the clinical symptoms of Parkinson’s disease? What is the typical age of onset?
A
- tremor
- slowness of movement
- rigidity and postural instability
- typical age of onset >56
13
Q
What are the pathological features of Parkinson’s?
A
- deposits of alpha-synuclein in the cell bodies and neurites lead to lewy bodies and lewy neurites
- loss of dopaminergic neurons in the substantia nigra leads to altered circuitry and loss of control of movement
14
Q
What causes Parkinson’s disease?
A
- 85-90% sporadic
- multifactorial
- factors such as oestrogen, smoking and drinking coffee may be protective
15
Q
What are some risk factors for Parkinson’s? (5)
A
- age
- male gender (3:1)
- some occupations such as farmers or welders
- exposure to heavy metals and toxins
- multiple susceptibility alleles
16
Q
Which genes are associated with genetic Parkinson’s?
A
- PARK 1 + 2 are involved in the production of alpha-synuclein. gain of function mutations can lead to increased deposits and oxidative stress
- PARK8 is involved in many processes such as protein interactions, kinases and GTPases and loss of function mutations are often seen in familial PD
- many more
17
Q
What do we still not knoe about Parkinson’s disease?
A
- early stages
- why are dopaminergic neurons so susceptible
- and if they’re so susceptible why does development take so many years
18
Q
What is currently done/attempted to tackle Parkinson’s disease?
A
- currently use treatments to minimise symptoms such as deep brain stimulation and L-DOPA
- other methods may be dopaminergic neuron replacement
- dopaine agonists
- clearing a-synuclein
- maintaining or restoring mitochondrial function
19
Q
What happens to the mitochondria in Parkinson’s?
A
- PARK 6 usually translocates out of the mitochondria into the cytoplasm
- mutations in its exit signal can cause it to stay in the mitochondria, ubiquitinate it and tag it for degradation
20
Q
What are the clinical symptoms of Huntington’s? What is the typical age of onset?
A
- uncontrolled muscle movement and spasms
- lack of coordination
- irritability and anxiety
- typical age of onset 40 with death 10 to 20 years post-diagnosis
21
Q
What are the pathological features of Huntingtons?
A
- loss of spiny neurons in the striatal medium
- alters circuitry and leads to involuntary movement
- aggregated huntingtin and ubiquitin
22
Q
What causes Huntington’s?
A
- mutations in the huntington gene that adds CAG repeats that make the huntingtin protein ‘sticky’ causing it aggregate
- the more repeats the earlier the age of onset
- autosomal dominant mutation
23
Q
What is currently done/attempted to treat Huntington’s?
A
- currently treat symptoms with drugs such as citalopram
- look into the replacement of neurons n the striatal medium
- clearance or stop the production of mutant huntingtin or target the processes affect by mut-huntingtin
24
Q
What are the clinical symptoms of ALS? What is the typical age of onset?
A
- loss of motor neurons in the brain and spinal cord
- progressive muscle weakness and loss
- difficulting speaking and eating
- leads to need for assisted ventilation and feeding
- typical age of onset 55 with death 5 years post-diagnosis
25
What causes ALS?
- mutations in SOD1 which protects against oxidative stress
- mitochondrial damage
- problems in genes involved in:
- RNA processing
- protein degradation
- cell signalling and trafficking
26
How can intronic mutations cause ALS?
- ccan affect RNA processing and produce altered protein products that can aggregate and be found in the brains of those with ALS
27
What has been done/atampted to tackle ALS?
- trials into oxidative stress have been unsucessful
- motor neuron placement?
- Riluzole can increase life span by up to 6 months by reducing glutamate excitotoxicity
28
How can we harvest neural stem cells?
- from the foetal brain
- from the few parts of the adult brain that has them but limited supply and cant get every cell type
- from pluripotent EScs treated with retionic acid to differentiate along with SHH = ventral differentation or BMP to give dorsal differentiation
29
Which neurodegenerative diseases are most feasible to treat with cell therapy/replacement at the moment?
- Parkinson's and Huntington's
- one cell type and localised
30
Where are stem cells to be implanted to treat HD or PD?
- in HD the stem cells are implanted into the striatal medium where the original loss occurs
- In PD they are also implanted in the SM despite damage being in the substantia nigra. this is beacause the neurons in the SN signal to the SM and so theres no need to implant new cells and make them form connections to the SM when you can just put them straight into the SM.
31
What are the current efforts/results in stem cell replacement for Huntington's?
- using foetal ESCs
- grafts don't show saftey concerns but also dont show any improvement after 6 months (fades)
- lots of cells are killed by immune rejection and those that survive dont recieve signals from surrounding endogenous cells and can have prion-like transmission of mut-HTT
32
What are the current efforts/results in stem cell replacement in Parkinson's
- using foetal ESCs
- grafts survive and show improvement only in younger patients
- diskinesias cause in 15% of people likely due to the fact that serotonin neurons are very easily harvested alongside dopaminergic ones and may be implanted
- needs immunosuppression
- prion like transmission of a-synuclein
33
What makes Alzhimer's more challenging to treat with cell therapy or replacement?
- wide spread damage
- not just one cell type
34
What makes ALS more challenging to traet with cell therapy or replacement?
- Although its one cell type its very widespread
- injection into the spinal cord is difficult and risky
- how to direct grafts to the right muscle?
35
Although cell therapy or replacement may not be yet feasible for AD or ALS how can stem cells help i n other ways? (4)
- immunomodulation
- trophic support
- promote neurite growth
- spinal injection of MSCs modified to overexpress GDNF can preserve leg function
36
How can stem cells be used to model neurodegenerative disease?
- can take cells from a patient iPSC reprogram them and differentiate them into the affected cell types to create a model for testing on drugs for example
37
What kinds of cells may be used as controls when modelling disease with stem cells?
- models made from cells of unaffected relatives
- cells taken from the patient and genetically modified to be of normal phenotype - isogenic controls
38
Why is reprogramming fibroblastast into iPSCs not always good for modelling neurodegenerative disease? How can this be fixed?
- cells age will be reset upon transformation
- can instead directly reprogram fibroblasts into neurons however this is a 1:1 conversion so expansion is not possible
39
How can we study age-related disease in vitro?
- induce ageing in culture
- increase stresses such as oxidative stress and DNA damage
- speed up maturation with astrocytes, cAMP and neurotrophic factors and telomerase inhibitors
- or via direct reprogramming
