The UPS in NDDs Flashcards
Maintaining proteostasis in neurons is especially important due to
– their complex architecture (ex. long axons)
– long lifespan
– inability to dilute aggregate load through cell division (no cell division therefore get stuck with issues)
The UPS is critical for functioning of neuronal synapses:
– Synaptic protein turnover
– Plasticity
– Long-term memory formation
Dysfunction of the UPS in NDDs can occur at…
- Impaired ubiquitination
- Loss of proteasome
- Disease-associated misfolded proteins inhibit the proteasome directly
- Secondary impairment of proteasome due to mitochondrial dysfunction
- aggravated by age-related decline of proteasomal catalytic activity
Impaired ubiquitination due to
– depletion or reduced activity of E1, E2, or E3 enzymes
– Ubb+1 (decreased recognition by UPS)
Result of loss of proteosome activity
results in accumulation of misfolded proteins, which can further impair catalytic activity
Secondary impariment of protesome due to mit damage
Mit damage/dysfunction leads to ATP depletion and ROS production –> increase number of abnormal proteins and inhibit proteosome
With age…
proteosomal catalytic activity is decreased
Misfolded proteins lead to a ___ in proteosome function
decrease/inhibition
How is cytotoxic mHTT removed
UNCLEAR
– soluble mHtt is not efficiently targeted by the 26S proteasome
– lack of efficient ubiquitination for proteasomal degradation leads to intracellular aggregation driven by the intrinsic disordered structure of mHtt
The data on proteasomal impairment in HD are contradictory
- mHtt impairs the UPS in cultured cells
- Proteasomes are not impaired in many animal models of HD
Impairment of UPS in HD has been attributed to:
– inefficient targeting of soluble mHtt for proteasomal degradation
– inhibition of 26S proteasome gate opening by soluble oligomeric mHtt species
mHTT inclusions (IBs)in the brains of HD patients and HD mice are ______ (deficient/enriched) in UPS components
enriched
– mHTT species can be initially tagged with Ub but are poor substrates for the proteasome
– suggest direct (mHtt protein) or indirect (proteins associated to mHtt) sequestration of the proteasome into the IBs
T/f: proteasome sequestration plays a major role in UPS dysfunction in HD
FALSE
as a large proportion of protesomes remain free (and still active)
More recent proposal of UPS and HD
global proteostasis network dysfunction: diffuse mHtt might inhibit the proteasome indirectly by saturating the protein folding machinery and diverting an excess of
other proteins to the UPS that then becomes impaired
Collapse of Proteostasis in HD
1) Chronic production of misfolded mHtt overwhelms chaperones
2) Chaperone exhaustion acts synergistically with aging
• decrease chaperone availability, leads to the misfolding and accumulation of other chaperone client protein
3) Misfolded proteins are diverted to the proteasome exceeding its capacity, and causing UPS impairment
3b) Mitochondria dysfunction limits ATP production and impairs energy-dependent protein clearance pathways (Autophagy)
4)Proteostasis collapse increases the levels of diffuse mHtt
mHTT can
- trigger apoptosis
* promote aggregation into inclusions bodies (IBs)
Inclusion bodies–short term vs long term role
Intially: IBs can extend survival by sequestering mHtt
Long term: IBs can recruit proteostasis components, in a vicious cycle that gradually disrupts cellular homeostasis that eventually culminates in necrosis
AD is characterized by
– presence of Ub in senile plaques and neurofibrillary tangles
– downregulation of E1 and E2 enzymes
– changes in E3 enzymes (e.g. reduction of Parkin)
– increased oxidation of DUB
– decreased proteasomal activity
Mutations in UPS in AD
A mutation in the Ub gene UBB+1 causes
neurodegeneration and is linked to AD
Proteasome and AD
- Proteasomes indirectly influence Ab production (as The UPS processes and degrades presenilin-1, presenilin-2 and b-secretase)
- Proteasome activation also clears tau
- Age-dependent decrease in proteasomal activity may cause both Ab and tau to accumulate
- Once Ab and tau aggregates are formed, they decrease proteasome activity –> creates a vicious cycle that increases Ab and tau accumulation
UBB+1
A frameshift form of Ub generated by
molecular misreading
- Ubb+1cannot be used for ubiquitynation
- seen in both AD and HD
T/F: Ubb+1 is only presented in demented individuals
FALSE
Ubb+1 mRNA is present in equal levels in non demented control individuals compared with AD patients
BUT it accumulates in AD patients’ neurons
Ubb+1 in AD patients
• Ubb+1 accumulates in neurons of all AD patients AND
colocalizes with dystrophic neurites of amyloid plaques and neurofibrillary
tangles
Ubb+ in healthy vs aging brain
In Healthy brain: Ubb+1 is continuously degraded by UPS In Aging or presence of UPS inhibitors: Ubb+1 degradation is affected and protein starts to accumulate
Aging and Ubb+
In aging or UPS inhibition Ubb+1 degradation is affected and Ubb+1 starts to accumulate which serves as a endogenous reporter for UPS dysfunction
–Causes Ubb+1 to shift from UPS substrate to inhibitor
– At high levels of Ubb+1 UPS fails to degrade Ubb+1 and Ubb+1 accumulation further induces functional impairment of UPS –> Proteasome inhibition causes neuronal
death
Parkin
E3 ligase that mediates multiple forms of ubiquitination, including K48- and K63-linked polyubiquitination
PD is caused by
Loss of parkin-catalyzed ubiquitylation is a cause of PD
Homozygous Parkin mutations: autosomal recessive juvenile- onset PD
Early studies into parkin show that
– Parkin targets ER-derived proteins and polyQ proteins for proteasomal degradation
– Parkin defect in the UPS-mediated protein quality control may be responsible for PD pathology
RECENT studies show
autophagy- related processes are pivotal to the pathology caused by Parkin mutations
When parkin is normal (WT) it localizes to
– Lewy bodies in sporadic PD patients
– aggresomes induced by proteasomal impairment
When parkin is mutated (ex. parkin-associated PD)
- devoid of Lewy bodies suggesting that parkin-mediated ubiquitination may be directly involved in the formation of Lewy bodies
- inability to form these protective inclusion bodies may underlie the rapid disease onset and progression (in familial PD with disorder parkin–i.e. juvenile onset PD)
