Lecture 18 - Autophagy 18 Flashcards
What diseases is Ubiquitin common in ?
Huntingtons
Parkinson’s
Alzheimers’
The protein that aggregates during disease effects the cells differently.
They all have dying neurones as the underlying.
What proteinopathies aggregate for each disease ?
Huntingtins aggregates in Huntington’s
alpha-synuclein in Parkinson’s
Amyloid B plaques in Alzheimer’s
What does neuronal-specific autophagy disruption in mice cause ?
Accumulation of ubiquitinated aggregates
Increased apoptosis
What happens in autophagy during neurodegeneration ?
Damaged mitochondria are selectively removed
Cells lacking autophagy accumulate protein aggregates
What causes Huntington’s disease?
Caused by polyglutamine (polyQ) expansion in Huntingtin protein.
An amplification of over 35 = disease-causing, under 18 = healthy. It decreases the stability of protein and makes it a higher frequency to fold.
This misfolding and aggregation cause Ubiquitination, which causes aggresome formation and therefore autophagic degradation.
What causes Parkinson’s?
Loss of dopinergic neurones .
The main neuropathology is aggregates of alpha-synclein (Lewy Bodies)
Kinase and Ubiquitin ligase recognise the damaged mitochondria and get rid of them.
Alpha-synclein mutations are rare, they are normally degraded by chaperone-mediated autophagy (fusion with a macrophage). Mutated versions blocks the CMA pathway, causing toxicity
What accumulates in Parkinson’s disease?
Damaged mitochiondria accumulate.
Mitochondria are rhe main soucre of Reactive Oxidative Species.
ROS damages cellular components
Hypothesis :
Parkinsons may be caused by mitochoondrial-derived oxidative damage
How do PARKIN and PINK1 regulate mitophagy?
PINK1 - mitochondrial kinase, early-onset Parkinson’s, it accumulates on depolarised mitochondria
PARKIN - Cystolic E3 ubiquitin ligase, mutated in 50% of autosomal recessive. 10-15% of sporadic early-onset Parkinson’s. It recruits onto depolarised mitochondria
What are some of the ways in which autophagy causes general neurodegenerative diseases ?
Impaired autophagosome formation:
PICALM - Alzheimer’s
alpha-syn,VPS35 - Parkinsons
Htt - Huntingtons
Disrupted lysosomal function:
PS-1 - Alzheimer’s
alpha-syn,VPS35 - Parkinsons
Secretion
Inhibited autolysosome formation
Autophagic cargo
Disruption of cargo recognition
How does Autophagy cause cancer?
Caused by an accumulation of DNA damage
Mutation in Atg6 gene is common in 40-75% of ovarian, breats and prostate carcinomas. Atg6 gene protects cells from DNA damage, its mutation stops it.
How can autophagy aide cancer growth ?
It helps tumour survive starvation becuase it is unregulated in hypoxic, nutrient-poor tumour regions.
What does blocking autophagy in cancer cause?
Blocking causes necrosis or apoptosis. Beclin1 causes the formation of autophagosomes. Bcl2 is on the surface of mitochondria and can block apoptosis.
How can autophagy be anti-oncogenic?
Cell homeostasis
Damage remoal
Reduced ROS/ genotoxicity
Reducing inflammation
How can autophagy be pro-oncogenic ?
Survival during oxygen or nutrient shortage
Prevention of apoptosis
Survival during chemotherapy
