Neurodegenerative Diseases Flashcards
What do neurodegenerative diseases stem from?
the loss of specific neurons in different parts of the NS
Which neurons degenerate in AD?
neurons in the hippocampus and certain regions of the cerebral cortex
Which neurons degenerate in PD?
dopaminergic neurons in the substantia nigra pars compacta
Which neurons degenerate in HD?
neurons in the striatum
What neurons die in stroke patients?
all those supported by an occluded or ruptured blood vessel
What is the striatum responsible for?
movement
What is AD characterised by?
the loss of learning and memory capacities and psychological changes and deficits
What percentage of AD and PD is sporadic?
95%
What are the major pathological features of AD?
- extracellular Aβ deposits in senile plaques
- intracellular neurofibrillary triangles (NFT)
What are APP mutations associated with?
- familial forms of early onset AD
- Cerebral Amyloid Angiopathy (CAA)
What is Aβ protein?
the main component of senile plaques and cerebrovascular amyloid deposits
What do mutations in Tau cause?
frontotemporal dementia with Parkinsonism associated with chromosome 17 i.e. aberrant forms of tau can give rise to neurodegeneration
What is the main component of NFTs?
hyperphosphorylated Tau
What is the number and distribution of NFTs correlated with?
the degree of dementia in AD
What does activation of protein kinase cdk5 contribute to?
tau phosphorylation and neuronal apoptosis
What are the major causes of early onset familial AD?
mutations in presenilin 1 and 2 that increase the proaction of 42-Aβ which has a high propensity for forming amyloid fibrils
What is the most common known genetic risk factor for AD after age 60?
inheritance of the E4 allele
What does the E4 allele do?
- promote the polymerisation of Aβ into plaque-forming fibrils
- impair neuronal regeneration or promote oxidative stress
How is Aβ generated?
through a serial cleavage of APP by β- and γ-secretase
What does the self-aggregation of Aβ do?
induce membrane lipid peroxidation which can impair the function of ion pumps and glucose transporters making neurons more sensitive to apoptosis
What are presenilins?
multiple membrane spanning proteins that are important for the processing of several proteins including APP and Notch
What do mutant presenilins do?
increase the production of Aβ as well as susceptibility to apoptosis
What does sAPP-α do?
decrease Aβ generation by directly associating with BACE1
What does BACE1 do?
process APP into sAPP-β and β-CTF, which is subsequently cleaved by the γ-secretase, producing Aβ
What is the γ-secretase complex formed of?
the sequential assembly of Aph1, nicastrin, presenilin, and Pen-2
What happens in the amyloidogenic pathway?
neurotoxic Aβ peptides are released after sequential cleavage of APP by β and γ-secretases, and further accumulate into oligomeric aggregates
What is Notch secretion dependent on?
NICD expression by γ-secretase
What is the amyloid cascade hypothesis?
- neurodegeneration in AD is caused by deposition of Aβ as amyloid plaques in brain tissue
- Aβ causes apoptosis directly in cultured neurons
- APP is a substrate of caspase-3 which cleaves APP to release a C-terminal apoptosis-inducing peptide
What is present in neurons associated with amyloid deposits?
- increased DNA damage
- increased cascade activity
- alterations in expression of apoptosis-related genes
What is PD associated with?
increased oxidative stress and mitochondrial dysfunction in dopaminergic neurons
What are pathological features of PD?
α -synuclein-rich Lewy bodies
What is MPTP?
a precursor to the neurotoxin MPP⁺, which causes permanent symptoms of PD by destroying dopaminergic neurons
What does inhibition of the ETC do?
generate ROS which damage cellular components and alter expression of redox sensitive transcription
What is ALS?
a progressively fatal degenerative disease of the motor neuron leading to paralysis and death
What are the 4 main genes that account for half of all fALS cases?
- C9orf72
- SOD1
- FUS
- TRADBP
What does the C9orf72 gene contain?
a hexanucleotide non-coding repeat expansion responsible for many cases of ALS and frontotemporal dementia
What is superoxide dismutase 1?
an antioxidant enzyme that protects the cell from ROS toxicity
What underlies the polyglutamine expansion disorders?
expansion of a polyglutamine (polyQ) tract
What is HD caused by?
expansion of a trinucleotide sequence (CAG) in the Huntingtin (HTT) gene
What are symptoms of HD?
- mood disorders
- lack of coordination
- unsteady gait
- hyperkinetic movements
What is HTT?
a large scaffolding protein with many interacting partners implicated in many processes e.g. transcription, signalling and transport
What are mutant HTT with polyQ extensions more prone to?
proteolytic cleavage that generates N-terminal fragments containing the polyQ (mHTT) with a tendency to undergo misfolding and aggregation, forming fibrillar aggregates
What do HTT aggregates do over time?
accumulate to form inclusion bodies within cells that interfere with neuronal function
What are TSEs?
infectious diseases transmitted via an abnormal form of the prion precursor protein (PrP)
What is prion?
a proteinaceous infectious particle
Give examples of human prion diseases
- CJD
- GSS
- fatal familial insomnia
- kuru
Give examples of animal prion diseases
- BSE
- TME
- FSE
What is the prion hypothesis?
normal cellular PrPC heterodimerises with PrPSC to induce transconformation
What can defects in or large numbers of UPS lead to?
the pathology of several neurodegenerative diseases
What is the known UPS dysfunction in AD, PD and HD respectively?
- AD = abnormal forms of UB1
- PD = loss of function mutation in Parkin
- HD = aggregates blocking proteosome function
What does balanced mitochondrial fusion and fission lead to?
- redox balance
- calcium handling
- ↑ ATP content
- ↑ spare respiratory capacity
What does unbalanced mitochondrial fusion and fission lead to?
- ROS overpowering
- calcium handling defects
- ↓ ATP content
- spare respiratory capacity
- mPTP opening
What does disturbed mtDNA lead to?
- increased oxidative stress
- disturbed mitochondrial genome
- impaired mitochondrial biogenesis
What do AD-causing PS1 mutations do?
have deleterious effects on mitochondrial function
What is a mechanism of nigral dopamine cell death in PD?
oxidative stress
What does accumulation of Aβ species do?
activate astrocytes and microglia which migrate to the site of plaque formation and penetrate the plaques which leads to production of pro-inflammatory cytotoxic molecules such as NO and TNF-α
What does sustained activation of microglia and other immune cells do?
exacerbate both amyloid and tau pathologies
What do Aducanumab and lecanemab do?
lower amyloid load and marginally delay worsening of dementia
What are the side effects of Aducanumab and lecanemab?
brain swelling and bleeding, or amyloid-related imaging abnormalities (ARIA)
Give examples of neurodevelopmental disorders in children caused by neurodegeneration
- Down’s syndrome
- lysosomal storage diseases
- various peroxisomal and mitochondrial disorders
- ciliopathies
- autism spectrum disorder
What is Rett syndrome?
a neurodevelopmental autism spectrum disorder of young females that arises due to epigenetic alterations
What is Rett syndrome characterised by?
profound cognitive impairment, communication dysfunction and postnatal growth defects
