WK9 - Mechanisms of Neurodegen.

Question 1

Why are neurons vulnerable/degenerative disease hard to treat?

Answer 1

1. Neurons are postmitotic (irreplaceable)
2. Long, delicate processes
3. High metabolic demands
4. Rely on proper connections
5. Limited cap. for repair and regen.

Question 2

How much volume is represented by the axon?

Answer 2

99%

Question 3

What mechanisms of neurodegeneration are we focused on?

Answer 3

1. Protein misfolding + aggregation
2. Gene mutations
3. Disrupted axonal transport
4. Metabolic stress/mitcohondrial dysfunction
5. Ageing
6. Enviro

Question 4

Gene mutations in ND

Answer 4

Many overlaps
* TDP43
* c9orf72 in ALS and FTD

Question 5

Ageing and ND

Answer 5

Incidence of AD and PD DOUBLES every 5y after age 65
* By age 90, 1/3 have some form of dementia or ND

Question 6

Environmental factors in ND

Answer 6

1. Chemo - influence and block axonal transport
2. Enviro neurotoxins - pesticides, polution, harder to study

Question 7

proteostasis

Answer 7

Protein homeostasis - essential for cellular health and depends on balanced protein synthesis, folding, trafficking, modification, and degradation.

Question 8

Molecular chaperones

Answer 8

Guide proper protein folding and help prevent misfolding.
* Help degrade aggregations

Question 9

Disruption of proteostasis

Answer 9

When protein quality control systems fail…
* Lose the original function of th protein AND get toxic aggregation

Question 10

Mitochondrial dysfunction (direct)

Answer 10

Mutations in proteins that regulate mitochondria can drive disease
* E.g. Parkin in PD

Question 11

Mitochondrial dysfunction (indirect)

Answer 11

Act downstream of other disease mechanisms
* contributing to progression.

Question 12

Mitochondria quality control systems

Answer 12

1. Mitochondrial biogenesis dynamics
2. Mitophagy

Question 13

PINK1 and Parkin mediated mitophagy

Answer 13

Mitochondria stressed > PINK1 cannot enter cell, not degraded
* expressed on surface
* Parkin sees this and accumulates ubiquitin proteins
* Signal autophagosome

Question 14

Mutations in PINK1 or Parkin

Answer 14

Disrupt mitophagy
* accumulation of damaged mitochondria
* dopaminergic n. loss
* PD

Question 15

Axonopathies

Answer 15

Primarily involve damage to axons
* AD
* PD
* ALS

Question 16

Wallerian degeneration

Answer 16

Past - considered passive response to loss of nutirents from cell body
Now - active, regulated process. Discovered unintentionally

Question 17

NMNAT2

Answer 17

Axonal enzyme
* lvls drop following axon injury
* ↑ of NMN, ↓ NAD
* This triggers activation of SARM1

Question 18

SARM1

Answer 18

Usually inactive
* When active > breaks down NAD
* NAD essential for energy metabolism
* ↓ NAD > ↓ energy
* -> DEGENERATION

Question 19

SARM1 and calcium dysregulation in Wallerian degeneration

Answer 19

Influx of calcium into axon > activates Calpains
* Break down the axonal cytoskeleton during Wallerian degeneration.

Question 20

What if SARM1 was deleted?

Answer 20

Neuroprotective
* Axon protection

Question 21

Biomarkers of axonal damage (and SARM1 activation)

Answer 21

1. Nfl - nonspecific
2. cADPR - specific

Question 22

NMNAT2 and SARM1 mutations in human disease

Answer 22

1. LoF mutations in NMNAT2 are associated with polyneuropathy in humans
2. GoF mutations in SARM1 are enriched in people with ALS and HSP

Question 23

Study role of pesticide called Vacor and SARM1

Answer 23

• Vacor causes axon degeneration
• SARM1 deletion stops degredation via Vacor