Neurodegenerative Diseases Flashcards
Parkinson’s Disease
Loss of substantia nigra
Dopamine release to Basal ganglia
Why is the substantia nigra lost?
Defects in mitophagy
The degradation of damaged mitochondria
Defects in Mitophagy
Mutations in key mitophagy proteins cause disease
- OPTN, TBK1 – familial ALS
- PINK1, Parkin, LRRK– familial Parkinson’s
- P62 – autophagy receptor (general) – ALS with frontotemporal dementia
Mitophagy
The degradation and clearance of damaged mitochondria
Mitochondrial functions in neurons
Signaling molecules
Axon branching
Regulation of cell death
Calcium homeostasis
ATP-dependent ion pumps
Biogenesis
Birth of new mitochondria
Fission/fusion dynamics
Exchange of mitochondrial materials
Mitochondria are damaged by activity
- Making ATP causes reactive oxygen species production
- ROS damages proteins and lipids in the mitochondria
Damaged organelles must be removed and replaced
Evidence for two types of mitophagy
- In the axon, damaged organelles are nonselectively packaged for degradation with other proteins and organelles
- In the cell body, selective mitophagy occurs
* Only mitochondria, not other things
Model of PINK1- PARKIN mediated mitophagy
- Under basal (healthy) conditions, PINK1 is cleaved by mitochondrial protease and degraded
- When mitochondria are unhealthy, PINK1 is not proteolytically cleaved and accumulates on the OMM
- PINK1 then activates PARKIN
- PARKIN ubiquitinates proteins on the mitochondria to start process of autophagy
* Step 1: engulf the organelle in an autophagosome membrane - Degrade the organelle
PINK1-PARKIN pathway
Accidental discovery, now the best characterized mitophagy pathway
- Loss of PINK1/Parkin has minimal/no effects on neurons in mouse models
- Loss of DA neurons in rat, fish, and fly models
- Hints at multiple pathways and perhaps species specific reliance on these proteins or the use of alternate mitophagy pathways
Mitochondria also actively move between neuronal compartments
Alzheimer’s Disease
- Progressive neurodegenerative disorder
- Impairs memory and other mental functions
- Most common type of dementia (60-80% of all dementia cases)
- A brain autopsy revealed the cerebral cortex was
generally thinned. The region that controlled
memory, language, judgement, and thinking was
severely impaired. Senile plaques were formed in
neurons, and tangles were found in nerve fibers
Alzheimer’s Pathology
Senile Plaques
* Extracellular
* Composed of cleaved Beta Amyloid
Neurofibrillary Tangles
* Intracellular
* Composed of Tau
Beta Amyloid (Aβ)
- Originates from the transmembrane protein APP (amyloid precursor protein)
- Normal Function of APP remains unclear
- APP is cleaved by secretases to form beta amyloid
- Abnormal aggregates of Aβ make up senile plaques
- Mutations in APP or secretases cause Early-Onset (hereditary) Alzheimer‘s Disease
Tau
- Microtubule Associated Protein important for microtubule stability
- In Alzheimer’s Disease, Tau forms aggregates which make up Neurofibrillary Tangles
Tau Structure
- Natively unfolded protein with very little structure
- In its normal state, tau binds and provides structure to microtubules
Tau Aggregation
- Hyperphosphorylation of tau inhibits its activity and leads to microtubule instability
- Hyperphosphorylation also promotes aggregation with other tau molecules
Amyloid Cascade Hypothesis
Amyloid aggregates cause damage to neurons
Improper APP processing
Increased amyloid beta aggregation
Impaired neuronal function,
inflammation and oxidative injury
Disruption of Tau and aggregation
Neuronal death
Amyloid Cascade Hypothesis Support
- Greatly increased Aβ levels in AD
- Mutations associated with Alzheimer’s disease promote amyloid aggregation
- Mutant APP in mice causes plaque formation and some mice show cognitive decline
Amyloid Cascade Hypothesis Problems
- Aβ accumulation does not correlate with neuronal loss and cognitive decline
- Treatments designed to target amyloid plaques have had little to no affect on Alzheimer‘s symptoms
Toxic Oligomer Hypothesis
Small Aβ oligomers have a toxic effect on neurons
There is evidence oligomers can:
* Bind receptors and disrupt cell signaling
* Disrupt synapses
* Impair Tau function
* Disrupt Calcium homeostasis
Tau Hypothesis
Tau is the primary cause of Alzheimer’s pathology
Supporting evidence:
* Tau has a known function in neurons that could cause harm if disrupted
* Tau aggregation correlates with dementia severity/ type of impairment
* Mutant tau animal models show neuronal loss that can be rescued with drugs that prevent Tau aggregation
Example Research on the Tau Hypothesis
Question: What causes Tau hyperphosphorylation?
Background/Hypothesis: The kinase GSK-3β is found
in Neurofibrillary tangles and may be the cause of
aggregate-promoting phosphorylation
Experiment: add GSK-3β to Tau Filaments in vitro
Result: tangle-like aggregates!
Conclusion: GSK-3β is a potential inducer of Tau
hyperphosphorylation and aggregation
Other hypotheses
- Neuroinflammation (aka an immune response) is key to Alzheimer’s pathogenesis
- Sleep deprivation increases Alzheimer’s risk
- Infectious pathogens as the cause of Alzheimer‘s Disease
