Autophagy modulation as a treatment of amyloid diseases

Zoe Mputhia, Eugene Hone, Timir Tripathi, Timothy Sargeant, Ralph Martins, Prashant Bharadwaj

Research output: Contribution to journalReview article

Abstract

Amyloids are fibrous proteins aggregated into toxic forms that are implicated in several chronic disorders. More than 30 diseases show deposition of fibrous amyloid proteins associated with cell loss and degeneration in the affected tissues. Evidence demonstrates that amyloid diseases result from protein aggregation or impaired amyloid clearance, but the connection between amyloid accumulation and tissue degeneration is not clear. Common examples of amyloid diseases are Alzheimer’s disease (AD), Parkinson’s disease (PD) and tauopathies, which are the most common forms of neurodegenerative diseases, as well as polyglutamine disorders and certain peripheral metabolic diseases. In these diseases, increased accumulation of toxic amyloid proteins is suspected to be one of the main causative factors in the disease pathogenesis. It is therefore important to more clearly understand how these toxic amyloid proteins accumulate as this will aide in the development of more effective preventive and therapeutic strategies. Protein homeostasis, or proteostasis, is maintained by multiple cellular pathways—including protein synthesis, quality control, and clearance—which are collectively responsible for preventing protein misfolding or aggregation. Modulating protein degradation is a very complex but attractive treatment strategy used to remove amyloid and improve cell survival. This review will focus on autophagy, an important clearance pathway of amyloid proteins, and strategies for using it as a potential therapeutic target for amyloid diseases. The physiological role of autophagy in cells, pathways for its modulation, its connection with apoptosis, cell models and caveats in developing autophagy as a treatment and as a biomarker is discussed.

LanguageEnglish
Article number3372
JournalMolecules
Volume24
Issue number18
DOIs
Publication statusPublished - 16 Sep 2019

Keywords

  • Alzheimer’s disease
  • Amyloid
  • Autophagy
  • Beta amyloid
  • Clearance
  • Huntington’s disease
  • Lysosome
  • Parkinson’s disease
  • Polyglutamine
  • Tau protein
  • Toxicity
  • α-synuclein

ASJC Scopus subject areas

  • Analytical Chemistry
  • Chemistry (miscellaneous)
  • Molecular Medicine
  • Pharmaceutical Science
  • Drug Discovery
  • Physical and Theoretical Chemistry
  • Organic Chemistry

Cite this

Mputhia, Z., Hone, E., Tripathi, T., Sargeant, T., Martins, R., & Bharadwaj, P. (2019). Autophagy modulation as a treatment of amyloid diseases. Molecules, 24(18), [3372]. https://doi.org/10.3390/molecules24183372
Mputhia, Zoe ; Hone, Eugene ; Tripathi, Timir ; Sargeant, Timothy ; Martins, Ralph ; Bharadwaj, Prashant. / Autophagy modulation as a treatment of amyloid diseases. In: Molecules. 2019 ; Vol. 24, No. 18.
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Mputhia, Z, Hone, E, Tripathi, T, Sargeant, T, Martins, R & Bharadwaj, P 2019, 'Autophagy modulation as a treatment of amyloid diseases', Molecules, vol. 24, no. 18, 3372. https://doi.org/10.3390/molecules24183372

Autophagy modulation as a treatment of amyloid diseases. / Mputhia, Zoe; Hone, Eugene; Tripathi, Timir; Sargeant, Timothy; Martins, Ralph; Bharadwaj, Prashant.

In: Molecules, Vol. 24, No. 18, 3372, 16.09.2019.

Research output: Contribution to journalReview article

TY - JOUR

T1 - Autophagy modulation as a treatment of amyloid diseases

AU - Mputhia, Zoe

AU - Hone, Eugene

AU - Tripathi, Timir

AU - Sargeant, Timothy

AU - Martins, Ralph

AU - Bharadwaj, Prashant

PY - 2019/9/16

Y1 - 2019/9/16

N2 - Amyloids are fibrous proteins aggregated into toxic forms that are implicated in several chronic disorders. More than 30 diseases show deposition of fibrous amyloid proteins associated with cell loss and degeneration in the affected tissues. Evidence demonstrates that amyloid diseases result from protein aggregation or impaired amyloid clearance, but the connection between amyloid accumulation and tissue degeneration is not clear. Common examples of amyloid diseases are Alzheimer’s disease (AD), Parkinson’s disease (PD) and tauopathies, which are the most common forms of neurodegenerative diseases, as well as polyglutamine disorders and certain peripheral metabolic diseases. In these diseases, increased accumulation of toxic amyloid proteins is suspected to be one of the main causative factors in the disease pathogenesis. It is therefore important to more clearly understand how these toxic amyloid proteins accumulate as this will aide in the development of more effective preventive and therapeutic strategies. Protein homeostasis, or proteostasis, is maintained by multiple cellular pathways—including protein synthesis, quality control, and clearance—which are collectively responsible for preventing protein misfolding or aggregation. Modulating protein degradation is a very complex but attractive treatment strategy used to remove amyloid and improve cell survival. This review will focus on autophagy, an important clearance pathway of amyloid proteins, and strategies for using it as a potential therapeutic target for amyloid diseases. The physiological role of autophagy in cells, pathways for its modulation, its connection with apoptosis, cell models and caveats in developing autophagy as a treatment and as a biomarker is discussed.

AB - Amyloids are fibrous proteins aggregated into toxic forms that are implicated in several chronic disorders. More than 30 diseases show deposition of fibrous amyloid proteins associated with cell loss and degeneration in the affected tissues. Evidence demonstrates that amyloid diseases result from protein aggregation or impaired amyloid clearance, but the connection between amyloid accumulation and tissue degeneration is not clear. Common examples of amyloid diseases are Alzheimer’s disease (AD), Parkinson’s disease (PD) and tauopathies, which are the most common forms of neurodegenerative diseases, as well as polyglutamine disorders and certain peripheral metabolic diseases. In these diseases, increased accumulation of toxic amyloid proteins is suspected to be one of the main causative factors in the disease pathogenesis. It is therefore important to more clearly understand how these toxic amyloid proteins accumulate as this will aide in the development of more effective preventive and therapeutic strategies. Protein homeostasis, or proteostasis, is maintained by multiple cellular pathways—including protein synthesis, quality control, and clearance—which are collectively responsible for preventing protein misfolding or aggregation. Modulating protein degradation is a very complex but attractive treatment strategy used to remove amyloid and improve cell survival. This review will focus on autophagy, an important clearance pathway of amyloid proteins, and strategies for using it as a potential therapeutic target for amyloid diseases. The physiological role of autophagy in cells, pathways for its modulation, its connection with apoptosis, cell models and caveats in developing autophagy as a treatment and as a biomarker is discussed.

KW - Alzheimer’s disease

KW - Amyloid

KW - Autophagy

KW - Beta amyloid

KW - Clearance

KW - Huntington’s disease

KW - Lysosome

KW - Parkinson’s disease

KW - Polyglutamine

KW - Tau protein

KW - Toxicity

KW - α-synuclein

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U2 - 10.3390/molecules24183372

DO - 10.3390/molecules24183372

M3 - Review article

VL - 24

JO - Molecules

T2 - Molecules

JF - Molecules

SN - 1420-3049

IS - 18

M1 - 3372

ER -

Mputhia Z, Hone E, Tripathi T, Sargeant T, Martins R, Bharadwaj P. Autophagy modulation as a treatment of amyloid diseases. Molecules. 2019 Sep 16;24(18). 3372. https://doi.org/10.3390/molecules24183372