Neurodegenerative Diseases

Question 1

Parkinson’s Disease

Answer 1

Loss of substantia nigra

Dopamine release to Basal ganglia

Question 2

Why is the substantia nigra lost?

Answer 2

Defects in mitophagy

The degradation of damaged mitochondria

Question 3

Defects in Mitophagy

Mutations in key mitophagy proteins cause disease

Answer 3

• OPTN, TBK1 – familial ALS
• PINK1, Parkin, LRRK– familial Parkinson’s
• P62 – autophagy receptor (general) – ALS with frontotemporal dementia

Question 4

Mitophagy

Answer 4

The degradation and clearance of damaged mitochondria

Question 5

Mitochondrial functions in neurons

Answer 5

Signaling molecules
Axon branching
Regulation of cell death
Calcium homeostasis
ATP-dependent ion pumps

Question 6

Biogenesis

Answer 6

Birth of new mitochondria

Question 7

Fission/fusion dynamics

Answer 7

Exchange of mitochondrial materials

Question 8

Mitochondria are damaged by activity

Answer 8

• Making ATP causes reactive oxygen species production
• ROS damages proteins and lipids in the mitochondria

Damaged organelles must be removed and replaced

Question 9

Evidence for two types of mitophagy

Answer 9

1. In the axon, damaged organelles are nonselectively packaged for degradation with other proteins and organelles
2. In the cell body, selective mitophagy occurs
   * Only mitochondria, not other things

Question 10

Model of PINK1- PARKIN mediated mitophagy

Answer 10

1. Under basal (healthy) conditions, PINK1 is cleaved by mitochondrial protease and degraded
2. When mitochondria are unhealthy, PINK1 is not proteolytically cleaved and accumulates on the OMM
3. PINK1 then activates PARKIN
4. PARKIN ubiquitinates proteins on the mitochondria to start process of autophagy
   * Step 1: engulf the organelle in an autophagosome membrane
5. Degrade the organelle

Question 11

PINK1-PARKIN pathway

Accidental discovery, now the best characterized mitophagy pathway

Answer 11

• 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

Question 12

Alzheimer’s Disease

Answer 12

• 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

Question 13

Alzheimer’s Pathology

Answer 13

Senile Plaques
* Extracellular
* Composed of cleaved Beta Amyloid

Neurofibrillary Tangles
* Intracellular
* Composed of Tau

Question 14

Beta Amyloid (Aβ)

Answer 14

• 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

Question 15

Tau

Answer 15

• Microtubule Associated Protein important for microtubule stability
• In Alzheimer’s Disease, Tau forms aggregates which make up Neurofibrillary Tangles

Question 16

Tau Structure

Answer 16

• Natively unfolded protein with very little structure
• In its normal state, tau binds and provides structure to microtubules

Question 17

Tau Aggregation

Answer 17

• Hyperphosphorylation of tau inhibits its activity and leads to microtubule instability
• Hyperphosphorylation also promotes aggregation with other tau molecules

Question 18

Amyloid Cascade Hypothesis

Amyloid aggregates cause damage to neurons

Answer 18

Improper APP processing
Increased amyloid beta aggregation
Impaired neuronal function,
inflammation and oxidative injury
Disruption of Tau and aggregation
Neuronal death

Question 19

Amyloid Cascade Hypothesis Support

Answer 19

• 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

Question 20

Amyloid Cascade Hypothesis Problems

Answer 20

• 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

Question 21

Toxic Oligomer Hypothesis

Small Aβ oligomers have a toxic effect on neurons

Answer 21

There is evidence oligomers can:
* Bind receptors and disrupt cell signaling
* Disrupt synapses
* Impair Tau function
* Disrupt Calcium homeostasis

Question 22

Tau Hypothesis

Tau is the primary cause of Alzheimer’s pathology

Answer 22

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

Question 23

Example Research on the Tau Hypothesis

Answer 23

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

Question 24

Other hypotheses

Answer 24

• 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