L5 - Specific loss of protein quality control during neurdegeneration

Question 0

Features and functions of Ubiquitin B

Answer 0

Features:
- highly conserved protein of 76 AA
- 5-8% of all protein degraded each day
- degradation is ATP-dependent
Functions:
- cellular homeostasis
- formation and synaptic function of neural networks

• GWAS suggest that ubiquitination is a key regulator in AD

Question 1

Genetic make-up is a risk factor for a minority of AD cases - what proportion?

Answer 1

• 3%f

Question 2

UBB binds to…

Answer 2

• a lysine in the substrate protein

Question 3

List proteasomal functions:

Answer 3

• deubiquitination
• accepting of substrate
• chaperoning/unfolding
• substrate entry
• release of aberrant proteins into the proteolytic core

Question 4

Which neurodegenerative disorders involve UBB+1 accumulation

Answer 4

• UBB+1 accumulates in the cellular hallmarks of taupathies but not in synucleinopathies

Question 5

Features of UBB+1

Answer 5

• cannot ubiquitinate, but can be ubiquitinated itself
• inhibits the proteasome dose-dependently
• impairs mitochondrial trafficking
• at high concentrations causes cell death
• induces heat-shock protein expression (HSP 40 & HSP 70)
• marker for proteasome impairment in a disease-specific manner and in non-neuronal cells and diseases (e.g. brain tumours, cardiac amyloidoses, steatohepatitis, inclusion-body myositis)

Question 6

Discoveries in UBB+1 mice

Answer 6

A high-expression UBB+1 mouse:

- memory deficits
- broad phenotypic screen revealed a respiratory deficit
- accumulation of UBB+1 in brainstem nuclei involved in the regulation of respiration (dorsal motor nucleus of vagus, nucleus of solitary tract medial)

Question 7

Relationship between UBB+1 and a-beta plaque load:

Answer 7

• UBB+1 reduces a-beta 42 plaque load in the cerebral cortex of an AD mouse line at 6 months

Question 8

How does UBB+1 achieve its effects on a-beta plaque load?

Answer 8

• via modulation of gamma-secretase (UBB+1 appears to increase its activity levels)

Question 9

Huntington’s disease - features and hallmarks:

Answer 9

• autosomal dominant due to CAG expansion in Huntingtin (chr.4)
• atrophy of affected brain areas (caudate, putamen, enlarged ventricles)
• aggregation of Huntingtin, UB and UBB+1 in INTRANUCLEAR occlusions
• expanded polyglutamines (Q35-40 and Q>40) + UB+1 lead to neurodegeneration

Question 10

UBB+1 and polyglutamine diseases:

Answer 10

• UBB+1 contributes to the pathogenesis of polyglutamine diseases in vitro
• neuronal intranuclear occlusions contain UBB+1 in both Huntington and spinocerebellar ataxia type 3
• UBB+1 mouse lines under lentiviral driven expression of expanded huntingtin constructs (Q43) in the striatum, develop significantly more neuronal inclusions