Neurodegenerative conditions Flashcards
Free radicals and ageing:
- What are the two types of free radicals?
- Endogenous sources of free radicals include
- Exogenous sources of free radicals include
- Two types of antioxidant defences:
Reactive oxygen species and reactive nitrogen species
Mitochondria, peroxidsomes, loxixygenases, NADPH oxidase, cytochrome P450
-UV light, ionising radiation, chemotherapy, inflammatory cytokines, environmental toxins
Enzymatic systems eg catalase, supraoxide dismutase, glutathione peroxidase
Non enzymatic systems eg. glutathione, vitamins (A, C, E)
Role of normal levels of free radicals?
Too little free radicals?
Too much free radicals?
Neuron development and function, LTP
Impaired cell proliferation and host defences
Random cellular damage, activation of certain signalling pathways –> cell death, disease and ageing
Why is the brain very sensitive to oxidative damage during ageing?
High metabolic demand
Low activity of antioxidative defence mechanisms
5 key hallmarks of ageing>
Mitochondrial dysfunction Telomere attrition Epigenetic alterations Loss of proteostasis Deregulated nutrient sensing
2 aspects of mitochondrial dysfunction that lead to ageing
Reduced efficiency of complexes I and IV of electron transport chain
Mutations in mito DNA
3 reasons why the mitochondira are vulnerable to the effects of ageing?
Highly oxidative microenvironment
Lacks histones, and limited mito DNA repair mechanisms –> lack of protection against DNA damage –> ageing
Do telomeres shorten with age?
Are telomeres susceptible to age related deterioration?
Yes
Yes
During ageing,
- Histones are ____
- There is global ________
- There is focal ______
Lost
hypomethylation
hypermethylation
Do epigenetic mechanisms protect from DNA damage?
Do abnormalities in histone modifying enzymes/chromatin remodelling lead to neurodegeneration?
Yes
Yes
2 ways ageing can contribute to epigenetic changes?
When mistakes in DNA rep occur, DNA repair proteins often need to remove epigenetic marks - which may not be replaced (correctly)
During DNA replication, epigenetic marks might not be copied correctly
What causes impaired protein folding?
Endogenous/exogenous stressors
What are the 4 ways that misfolded proteins are dealt with
Autophagy - macroautophagy and chaperone mediated autophagy
Proteasomal degradation
Chaperone mediated folding
Aggregation and ageing
During ageing, what happens to these pathways?
Autophagy and proteasomal degradation pathways are impaired –> more protein aggregation and ageing
Deregulated nutrient sensing - what two pathways and direction?
IGF1 and mTOR
Impaired –> extended lifespan
More info on deregulated nutrient sensing in notes?
Yes
4 other hallmarks?
Cellular senescence
Stem cell exhaustion
Altered intracellular communication
Genomic instability
Are most neurodegenerative disorders sporadic, rather than genetic?
Yes
4 sporadic and 2 genetic neurodegenerative diseases?
Alzheimers, Parkinson’s, ALS, Creutzfeldt Jakob disease
Huntington’s disease, spinal muscular atrophy
Common features of neurodegenerative diseases?
Delayed onsent Most have unknown etiology Abnormal protein processing and aggregation Selective neuronal vulnerability Cellular toxic effects
Pathogenesis features?
Defective protein handling/degradation Accumulation of abberant/misfolded proteins Abberant epigenetic mechanisms Metabolic dysfunction Neuroinflammation
More info on reactive microglia?
Yes
Contrast dementia and mild cognitive impairment
Dementia is loss of memory plus other impairments, causes impared function in daily life
Mild cognitive impairment is loss of memory only, doesn’t cause impaired function
Do notes have definition for MCI for American Academy of Neurology?
Yes
Yes
