Parkinson's Disease Flashcards
What NT release is effected in Parkinson’s disease?
dopamine
What is parkinson’s pathology?
loss of substantia nigra
Why is the substantia nigra lost?
degradation of damaged mitochondria
How are damaged mitochondira degraded?
degraded by autophagosomes (lysosomes)
- mitochondria engulfed by ubiquitin (proteins on mitochondria membrane)
What key mitophagy protein mutations cause disease
- OPTN, TBK1 - familial ALS
- PINK1, Parking, LRRK - familial Parkinson’s
- P62 autophagy receptor - ALS with frontotemporal dementia
What are functions of mitochondria in neurons?
- ATP
- ATP-depended ion pumps
- signaling molecules
-axon branching - regulation of cell death
- calcium homeostasis
What are the different mechanisms of mitochondrial maintenance?
Biogenesis
- birth of new mitchondria
Fission/fusion dynamics
- exchange of mitochondrial material
Mitophagy
- degradation of damaged organelles
Why do you need mitophagy?
- prevent mixing of damaged components with other mitochondria via fusion
- prevent toxic compounds from leaking into the cell
- prevent release of apoptotic proteins like cytochrome C which will elicit neuron cell death
How are mitochondria damaged?
By activity
- making ATP causes reactive oxygen species production
- ROS damages proteins and lipids in the mitochondria
What is the model of PINK1-Parking mediated mitophagy
- under basal (healthy) conditions, PINK1 cleaved by mitochondiral protease and degraded
- under unhealthy conditions, PINK1 not proteolytically cleaved and accumulates on the OMM (outer membrane)
- parking ubiquitinates proteins on mitochondria to start autophagy process (engulf organelle)
- degrade organelle
Mitochondrial homeostasis in neurons is critical for their survival and function. This is a mechanism we discussed to maintain mitochondrial poopulations?
fission/fusion dynamics
biogenesis
mitophagy
Mutations in what gene cause Parkinson’s disease due to disrupting mitophagy?
Pink and Parking
