Autophagy in NDDs Flashcards
Autophagy protects against neurodegeneration by eliminating two hallmarks of NDDs:
– defective mitochondria
– toxic protein aggregates
Why are dmaaged mitochondria bad & contribute to NDDs
– produce high levels of reactive oxygen species (ROS)
– pose a threat to cellular components (proteins, lipids and DNA)
Why are protein aggregates bad and contribute to NDDs
–exacerbated by ROS- mediated oxidative damage
– compromise the function of organelles
– are particularly toxic for neurons
link b/t autophagy and NDDs
Reduced autophagy (age- related, pharmacologically or genetically caused) increases the risk of NDDs
These Markers of dysfunctional autophagy are detected in samples from patients with NDDs
– autophagosome accumulation
– limited degradation of p62 (autophagy receptor normally degraded by autophagy)
Deletion of Atg5 or Atg7 in the mouse CNS during embryonic development results in
neurodegeneration
KO of these genes causes early degen
How can we use autophagy to treat NDDS
By Pharmacologically stimualting autophagy–potential therapeutic strategy against NDDs
Autophagy in HD
Disruptions in autophagy are thought to contribute to the pathogenesis of HD
• Catch 22: autophagy is required for clearance of aggregated proteins, but mHTT interrupts the process (i.e. autophagy clears aggregates but mHTT + aggregates interrupt autophagy)
Brains of HD patients (and rodent models) contain
contain an excessive number of autophagosomes
In HD, autophagy is affected at several steps:
- defect in cargo loading
- trafficking of autophagosomes
- decreased fusion between autophagosomes and lysosomes
Alterations in autophagosomes in HD
- The ability of autophagosomes to recognize cytosolic cargos is largely defective in HD cells (autophagosomes appear “empty”)
- mHTT disrupts autophagosome motility and prevents autophagosome
fusion with lysosomes
Aberrant binding of mHtt to p62
- shields p62 binding site
* prevents selective recognition of mitochondria, lipid droplets, and cytosolic aggregates of mHtt
Autophagy in AD (
AD brains contain numerous immature
autophagasomes particularly in dystrophic neurites
T/F: Autophagy has a clear role in AD
FALSE
• Inconsistent evidence of the role of autophagy:
– evidence of roles in Ab clearance AND role in A-beta production
Nature of the autophagic dysfunction in AD
Is unclear (and opposing!!)
- impaired autophagy initiation
- Increased autophagy initiation
- impaired cargo degradation
How Ab can regulate autophagy:
– Ab increase autophagy (activation of AMPK)
– Aβ42 compromises the function of AMPK and impedes initiation of autophagy
– Ab decreases autophagosome clearance
Autophagy over the disease course
• Initially autophagy may be protective by clearing:
– toxic Aβ species (aggrephagy)
– injured lysosomes (lysophagy)
• BUT in Advanced disease: toxic burden exceeds cellular reparative capacity: neuronal death may follow
May be initially helpful, but pathogenic processes may eventually compromise the
impermeability of endolysosomal compartments
Autophagy in PD
- Autophagy is disrupted at multiple stages in PD
- Autophagosomes accumulate when mutant or even WT α-synuclein is overexpressed in transgenic mice
Wildtype vs. mutant alpha-synucleuin
- Wt α-synuclein is degraded by CMA
- Mutant α-synucleins are degraded by autophagy
- CMA is compromised in PD –> leads all forms of α-synuclein become degraded by autophagy
• Autophagosomes accumulate when mutant or even WT α-synuclein is overexpressed in transgenic mice
How autophagy leads to excess intracellular levels of α-synuclein
– impairs autophagosome biogenesis by interfering with PAS formation
– decreases lysosomal acidification and slows lysosomal protein turnover
PD & lysosomes
Some patients develop PD due to loss-of-function mutations of lysosomal ATPase
– cells with high lysosomal pH
– proteolytic failure
Mitophagy
selective degradation of mitochondria by autophagy
Mitochondrondrial dysfunction in PD
Mitochondrial dysfunction is a major pathological feature in PD
- Abnormal mitochondria are eliminated through mitophagy
Pink and Parkin
Pink and Parkin are essential for mitophagy
But are mutated in familial PD and decrease mitophagy
T/F: mitophagy is the cause of sporadic and familial PD
FALSE
•The relevance of decreased mitophagy in sporadic PD is unclear
PINK1
- a serine-threonine kinase
- associates + accumulates in outer memb of damaged mitochondria
- PINK1 phosphorylates Ub conjugated to mitochondrial proteins leading to parkin translocation
PARKIN
– E3 ubiquitin ligase that normally localizes in the cytosol
– is recruited to and retained on the mitochondria due to higher affinity with phosphorylated Ub
- parkin brings more Ub –> generates long chains of ubiquitin allow recognition by autophagy receptor –> sent to phagophore for degradation
PINK1 and parkin work togetehr
- PINK1 associates + accumulates in outer memb of damaged mitochondria then phosphorylates Ub conjugated to mitochondrial proteins leading to parkin translocation
- Parkin brings more Ub –> generates long chains of ubiquitin allow recognition by autophagy receptor –> sent to phagophore for degradation
Alterations in PINK1 and Parkin
Mutations in the genes encoding PINK1 and parkin account for the majority of autosomal-recessive cases of PD
– More than 100 loss-of function mutations have been identified in the PARKIN gene
Pink and/or parkin mutations impede mitophagy
– damaged mitochondria accumulate
– initiate apoptosis through:
–> the intrinsic pathway
–> ROS–mediated oxidation of membrane lipids and lysosome membrane destabilization
