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PMCOL 412 > Targeting Autophagy to Treat Neurodegenerative Diseases > Flashcards

Targeting Autophagy to Treat Neurodegenerative Diseases Flashcards

1
Q

Targeting Autophagy in NDDs

A

For most NDDs the available evidence favors a strategy of enhancing the efficacy of autophagy
• Treatment with rapamycin provided a proof of principle

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2
Q

Limitations in targeting autophagy in NDDs

A
  • Strategy might not work is cargo recognition by the autophagosome is impaired (if cargo isn’t recognized –> increased autophagy isn’t helpful)
  • Timing is very important
  • Inducing autophagy if autophagy flux is inhibited may have serious detrimental effects (more autophagosome that cannot be cleared = worsens the issues)
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3
Q

Enhancing Protein Clearance by Activating Autophagy through

A
  • mTOR inhibitors
  • AMPK activators
  • Inositol lowering agents
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4
Q

mTOR inhibitors

A

Rapamycin

Kinase inhibitors

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5
Q

AMPK activators

A
  • Metformin

- Trehalose

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6
Q

Inositol Lowering agent

A

lithium

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7
Q

Rapamycin (Sirolimus)

A

Rapamycin: Antibiotic with antifungal and

immunosuppressive properties

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8
Q

How rapamycin binds

A
  • Rapamycin works by an allosteric mechanism: Does not bind to the kinase domain (activation loop)
  • Rapamycin binds to the cytoplasmic receptor FKBP12
  • FKBP12-rapamycin complex binds to mTOR
  • FKBP12-rapamycin complex destabilizes mTORC1
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9
Q

T/F: Rapamycin does NOT impair kinase activity directly

A

TRUE

binds to the FKP12 receptor rather than the activation loop

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10
Q

Kinase Inhibitors of mTOR

A
  • Selective ATP-competitive small molecule directly inhibit the kinase domain of mTOR
  • gets into activation loop and directly inhibits kinase activity
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11
Q

Kinase inhibitors vs. Rapamycin

A

Autophagy induction by ATP-competitive
inhibitors is higher than by rapamycin
- but rapamycin has been widely used in humans (safe for human use)

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12
Q

Rapamycin facilitates autophagy through

A

– induction of autophagy initiation (ULK complex)

– enhancement of lysosomal biogenesis (enhances TFEB translocation to nucleus)

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13
Q

mTOR inhibitors is complicated because

A
  • Use of mTOR inhibitors is complicated due to mTOR effects independent of autophagy
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14
Q

non-autophagy effects of mTOR

A
  • mTOR regulates translation and cell growth, and whole-body metabolism)
  • treatment with rapamycin impairs wound healing and has immunosuppressive effects
    (prevent its use in infectious diseases and immunosuppressed individuals)
  • Treatment not ideal for chronic diseases
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15
Q

Rapamycin in AD

A 
• In AD rapamycin is an effective inhibitor of
neurodegeneration in mouse models of AD
– improves AD-linked cognitive deficits
– reduces Aβ accumulation
– Attenuates tau hyper-phosphorylation
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16
Q

Success of any autophagy induction intervention may depend on the…

A

TIMING

– Should be performed very very early, before Ab accumulation

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17
Q

Rapamycin use in HD: results

A

Studies on cellular models gave promising results indicating a possibility to enhance degradation of aggregated proteins

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18
Q

In animal experiments rapamycin caused:

A

– a decrease in levels of mHTT aggregates
– amelioration of neurodegeneration
– Improved animal behavior

19
Q

Timing for rapamycin use

A
  • Rapamycin is effective at early stages of protein aggregation
  • When aggregates become highly stable they seem to be too large to be degraded by autophagy
20
Q

Downsides of rapamycin use in HD

A
  • Autophagy activators may have a limited beneficial effect if cargo recognition is defective
  • Despite these encouraging results clinical trials with the use of rapamycin for treatment of HD have not been started yet
21
Q

Metformin: drug type

A
  • Prototypical activator of AMPK

- Widely used anti-diabetic agent

22
Q

Metformin & autophagy

A

INDUCES autophagy
• Some of the effects of Metformin in diabetes may be mediated via autophagy
• Worth considering use if autophagy upregulation is beneficial
• Mediates multiple AMPK-unrelated effect

23
Q

Metformin in NDDs

A
  • Metformin abrogated α-synuclein toxicity in primary cultures of cortical neurons
  • Metformin reduced neuronal loss in a neurochemical lesion model of PD in mice
  • In metformin-treated neurons, hyperphosphorylated tau and Aβ were reduced
24
Q

Trehalose: what is it

A

is a a disaccharide present in bacteria, yeast, fungi and plants but not in vertebrates

25
Q

How trehalose works

A
  • It affects mTOR-independent regulation of autophagy

- It also affects mTOR-dependent regulation of autophagy

26
Q

Trehalose: mTOR-independent regulation of autophagy

A

– induces TFEB translocation to the nucleus:
• Enhances expression of autophagy-related genes (Beclin1, p62, LC3, etc)
– activates AMPK which activates the ULK complex

27
Q

Trehalose: mTOR-dependent regulation of autophagy

A

– activates AMPK, which inhibits mTOR

28
Q

Mettformin in human us: retrospective studies

A

Retrospective studies with Metformin use for more than 2 years:
– significant reduction in neurodegenerative disease
– neuroprotective
– promotes neurogenesis

29
Q

Metformin in human observational studies

A

Multiple observational studies reported varying results on the value of metformin for preventing AD in DMT2 patients
– Three studies reported a decreased risk for cognitive impairment or dementia
– One meta-analysis suggested a trend for reduced risk of dementia with metformin use in diabetics
– Three other studies reported an increased risk for impaired cognitive performance, dementia, or AD
– One study reported that longer metformin use was associated with an increasing risk for dementia
MIXED results

30
Q

Regulation of AMPK by Trehalose

A
  • Trehalose inhibits a family of glucose transporters (SLC2A) generating a starvation-like state
  • trehalose competes with sugar at the transporters –> prevent sugar entry –> decrease ATP –> AMPK activated
31
Q

AMPK & autophagy

A
  • Low energy levels (high AMP) stimulates autophagy through AMPK
32
Q

Inhibiting AMPK effects

A

fructose/glucose entry increases ATP –> inhibits AMPK –> activates mTOR –> no autophagy

33
Q

Trehalose–regulation of AMPK

A

Low energy levels (high AMP) stimulates autophagy through AMPK –> mimicked by trehalose (by competing with sugars for entry and decreasing ATP)–> AMPK phosphorylates and activates of ULK1 + inhibits mTOR –> autophagosome biogenesis

34
Q

Trehalose in Models of NDDs

A

Trehalose enhances the removal of misfolded proteins in several neurodegenerative models

35
Q

Trehalose in cellular vs. animal models

A
    • Trehalose proved effective in cellular models of PD, HD and AD –> In cultured cells trehalose decreases cytosolic aggregates of mHtt, a- synuclein and p- tau
    • Trehalose was also effective in mouse models of HD, AD and tauopathies–> In animal models it cleared aggregates, reduced neurodegeneration and ameliorated motor and cognitive performance
36
Q

Trehalose for Human Therapy: issues

A

approved for human use BUT issues with availability

  • Uncertainty if trehalose crosses BBB or enter neurons –> requires transporter not expressed in neurons
  • Trehalose cannot be delivered orally in humans– because it is degraded by trehalase, an enzyme present in the gastrointestinal tract
37
Q

Trehalose use in humans: how to make it work

A

Nanolipid-trehalose conjugated have been developed
– effective autophagy inducers
– overcome the poor pharmacokinetics of this sugar

38
Q

Lithium: as a therapeutic agent

A
  • Lithium inhibits inositol monophosphatase
  • Lithium also activates AMPK
  • Lithium has effects independent of autophagy
39
Q

T/F: lithium Lithium induces autophagy through mTOR

A

FALSE

Lithium induces autophagy independent of mTOR

40
Q

How lithium works

A
  • Lithium prevents inositol recycling, which leads to depletion of cellular inositol and inhibition of the phosphoinositol cycle
  • Inositol and IP3 are negative regulators of
    autophagosome production
    THEREFORE lithium increases autophagy by depleting cellular inositol
41
Q

Lithium in Models of NDDs

A

Lithium enhances the cellular clearance of aggregate-prone forms of huntingtin, α-synuclein, tau and SOD1 in cellular models

42
Q

Lithium efficacy against NDDs

A

Lithium has neuroprotective effects in most NDDS, similar to rapamycin
– It ameliorates motor function in a mouse model of tauopathy
– It slows disease progression in HD models

43
Q

lithium as a combination therapy

A

Effects are additive to rapamycin, metformin and other autophagy enhancers

44
Q

Human use of lithium

A

–> Lithium used off-label in experimental therapy in 3 HD patients–> each patient showed different results
– some neurological parameters were improved, but no changes in chorea
could be or viceversa
– Problem: all these patients received also other drugs

Other clinical trials with HD patients also did not give conclusive results: extremely different responses of various persons

PMCOL 412 (35 decks)

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