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The diverse roles of TIMP-3: Insights into degenerative diseases of the senescent retina and brain

The diverse roles of TIMP-3: Insights into degenerative diseases of the senescent retina and brain
The diverse roles of TIMP-3: Insights into degenerative diseases of the senescent retina and brain
Tissue inhibitor of metalloproteinase-3 (TIMP-3) is a component of the extracellular environment, where it mediates diverse processes including matrix regulation/turnover, inflammation and angiogenesis. Rare TIMP-3 risk alleles and mutations are directly linked with retinopathies such as age-related macular degeneration (AMD) and Sorsby fundus dystrophy, and potentially, through indirect mechanisms, with Alzheimer's disease. Insights into TIMP-3 activities may be gleaned from studying Sorsby-linked mutations. However, recent findings do not fully support the prevailing hypothesis that a gain of function through the dimerisation of mutated TIMP-3 is responsible for retinopathy. Findings from Alzheimer's patients suggest a hitherto poorly studied relationship between TIMP-3 and the Alzheimer's-linked amyloid-beta (Ab) proteins that warrant further scrutiny. This may also have implications for understanding AMD as aged/diseased retinae contain high levels of Ab. Findings from TIMP-3 knockout and mutant knock-in mice have not led to new treatments, particularly as the latter does not satisfactorily recapitulate the Sorsby phenotype. However, recent advances in stem cell and in vitro approaches offer novel insights into understanding TIMP-3 pathology in the retina-brain axis, which has so far not been collectively examined. We propose that TIMP-3 activities could extend beyond its hitherto supposed functions to cause age-related changes and disease in these organs.
TIMP-3, ECM, AMD, Sorsby, retina, Alzheimer’s disease, Dementia
2073-4409
Dewing, Jennifer M.
4c4af0cf-b622-4f1c-aced-51a844e60475
Carare, Roxana-Octavia
0478c197-b0c1-4206-acae-54e88c8f21fa
Lotery, Andrew
5ecc2d2d-d0b4-468f-ad2c-df7156f8e514
Ratnayaka, J. Arjuna
002499b8-1a9f-45b6-9539-5ac145799dfd
Dewing, Jennifer M.
4c4af0cf-b622-4f1c-aced-51a844e60475
Carare, Roxana-Octavia
0478c197-b0c1-4206-acae-54e88c8f21fa
Lotery, Andrew
5ecc2d2d-d0b4-468f-ad2c-df7156f8e514
Ratnayaka, J. Arjuna
002499b8-1a9f-45b6-9539-5ac145799dfd

Dewing, Jennifer M., Carare, Roxana-Octavia, Lotery, Andrew and Ratnayaka, J. Arjuna (2019) The diverse roles of TIMP-3: Insights into degenerative diseases of the senescent retina and brain. Cells, 9 (1), [39]. (doi:10.3390/cells9010039).

Record type: Review

Abstract

Tissue inhibitor of metalloproteinase-3 (TIMP-3) is a component of the extracellular environment, where it mediates diverse processes including matrix regulation/turnover, inflammation and angiogenesis. Rare TIMP-3 risk alleles and mutations are directly linked with retinopathies such as age-related macular degeneration (AMD) and Sorsby fundus dystrophy, and potentially, through indirect mechanisms, with Alzheimer's disease. Insights into TIMP-3 activities may be gleaned from studying Sorsby-linked mutations. However, recent findings do not fully support the prevailing hypothesis that a gain of function through the dimerisation of mutated TIMP-3 is responsible for retinopathy. Findings from Alzheimer's patients suggest a hitherto poorly studied relationship between TIMP-3 and the Alzheimer's-linked amyloid-beta (Ab) proteins that warrant further scrutiny. This may also have implications for understanding AMD as aged/diseased retinae contain high levels of Ab. Findings from TIMP-3 knockout and mutant knock-in mice have not led to new treatments, particularly as the latter does not satisfactorily recapitulate the Sorsby phenotype. However, recent advances in stem cell and in vitro approaches offer novel insights into understanding TIMP-3 pathology in the retina-brain axis, which has so far not been collectively examined. We propose that TIMP-3 activities could extend beyond its hitherto supposed functions to cause age-related changes and disease in these organs.

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Accepted/In Press date: 19 December 2019
e-pub ahead of print date: 21 December 2019
Published date: 21 December 2019
Keywords: TIMP-3, ECM, AMD, Sorsby, retina, Alzheimer’s disease, Dementia

Identifiers

Local EPrints ID: 436949
URI: http://eprints.soton.ac.uk/id/eprint/436949
ISSN: 2073-4409
PURE UUID: f1f1bbb8-c382-484c-96f4-cbdc8f1543a8
ORCID for Roxana-Octavia Carare: ORCID iD orcid.org/0000-0001-6458-3776
ORCID for Andrew Lotery: ORCID iD orcid.org/0000-0001-5541-4305
ORCID for J. Arjuna Ratnayaka: ORCID iD orcid.org/0000-0002-1027-6938

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Date deposited: 14 Jan 2020 17:32
Last modified: 26 Nov 2021 03:01

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Contributors

Author: Jennifer M. Dewing
Author: Andrew Lotery ORCID iD

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