Targeting the UPS to Treat NDDs Flashcards

1
Q

Areas to target the UPS for treatment of NDDs

A
  • Stimulate Ubiquitylation
  • inhibit DUB
  • Increase proteasome proteolytic capacity
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2
Q

PROTACS

A

AKA PROteolysis-Targeting Chimeras

– heterobifunctional molecules with a Protein binding site, E3 ligase binding site and flexible chemical linker

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3
Q

Structure of PROTACS

A

Protein of interest (POI)-binding site and E3 ligase binding site bound together through flexible chemical linker

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4
Q

Binding to Protacs

A

POI binding site binds target protein –> Binding induces induce artificial ubiquitination, leading to and degradation of the protein by the proteasome

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5
Q

First vs. second gen PROTACs

A
  • First generation Protacs too bulky to get into cells (therefore not super successful)
  • Second generation of Protacs: non-peptide, small molecules membrane-permeable
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6
Q

PROTACS in HD

A
  • Under investigation in cellular models of HD (patient fibroblasts)
  • Benefit: tissue specificity by developing molecules that recruit E3 ligases only expressed in a certain tissue
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7
Q

PROTACS in AD

A

Patent for PROTAC of tau binding moieties linked to E3 ligase binding moiety (thalidomide)
– can induce ubiquitination of tau protein and promote its degradation in cells

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8
Q

Targeting DUBs

A

Targeting DUBs is the easiest way to increase UPS activity

– DUBs are the most druggable enzymes within UPS

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9
Q

DUB function

A

DUBs acting upstream of the proteasome may act as a “rescue crew”
– they salvage specific substrates by deubiquitination before they are engaged in degradation

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10
Q

DUB inhibition

A

DUB inhibitors may accelerate the turnover of the specific substrate for proteasome-mediated degradation

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11
Q

Inhibition of UPS14

A

Inhibiting the catalytic activity of USP14 may have therapeutic benefits in NDDs
as it increases protosomal degradation by preventing premature deubiquitination

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12
Q

USP24 function

A

USP14 is responsible for trimming Ub chains on substrates destined for degradation and thus recycling mono-Ub

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13
Q

USP14 binding area

A

USP14 and UCHL5 associate reversibly to the 19S lid

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14
Q

Premature USP14 activation

A

Premature deubiquitination by USP14 can

prevent protein degradation

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15
Q

USP14 Inhibitors in NDDs

A
  • USP14 inhibitors are under development for the clearance of aggregation-prone proteins
  • Extent of USP14 contribution to the clearance of proteins involved in neurodegeneration in vivo remains controversial
    – Inactivation or depletion of USP14 may not be beneficial in all NDDs
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16
Q

Drawbacks of USP14 inhibitors

A

Potential drawbacks because USP14 loss causes severe morbidity and postnatal lethality in mice

17
Q

IU1

A
  • USP14 inhibitor
  • small molecule with remarkable specificity
    against USP14
18
Q

IU1 was discovered by

A

– identified by high-throughput screening

19
Q

IU1 function

A

Enhances clearance of disease-linked proteins in cultured cells in a proteasome- dependent manner:
– Tau, ATXN3

20
Q

T/F: IU1 has been shown to prevent ND in vivo

A

FALSE
It remains to be determined if IU1 can prevent
neurodegeneration in vivo

21
Q

Acute effects of USP inactivation

A

Acute inactivation of USP14 could

increase degradation of some disease proteins without perturbing Ub homeostasis

22
Q

Chronic effects of USP inactviation

A

Chronic inactivation of USP14 could cause an overall disturbance in mono-Ub availability that leads to compensatory mechanisms of protein turnover
lack of mono-Ub –> can’t tag for degradation –> new mechanism

23
Q

Nrf1 and Nrf2

A
  • are transcription factors for
    proteasome genes
  • Nrf1 and Nrf2 are also substrates of proteasomal degradation
24
Q

Nrf1 activity

A

Nrf1 only becomes active in the nucleus when increased UPS function is required

when only need low UPS –> Nrf1 isn’t active

25
Q

Nrf2 activity

A

regulates the antioxidant response
• stimulates expression of proteasome subunits
• drives the synthesis of lysosomal proteins

is regulated by ox. stress

26
Q

Sulforaphane

A

small molecule that induces Nrf2
– Induces proteasomal genes
– Increases proteasome levels and activity
– enhances UPS function in vivo

27
Q

Sulforaphane for HD

A

proposed treatment

- reduces mutant huntingtin protein and mitigate polyQ toxicity in neuronal cells

28
Q

Sulforaphane Function

A

SFN increased Nrf2 accumulation and nuclear translocation –> goes to nuclues –> increase proteasomal genes –> enhances UPS function

29
Q

In short:
stimulating ubquitylation is down by ____.
___ inhibits DUB.
___ increases proteolytic capacity

A

PROTAC
IU1 (through USP14 inhibition)
Sulforaphane (by increasing Nrf2)