Connecting TDP-43 Pathology with Neuropathy

Joseph R. Klim; Greta Pintacuda; Leslie A. Nash; Irune Guerra San Juan; Kevin Eggan

doi:10.1016/j.tins.2021.02.008

Connecting TDP-43 Pathology with Neuropathy

Joseph R. Klim, Greta Pintacuda, Leslie A. Nash, Irune Guerra San Juan, Kevin Eggan^*

^*Corresponding author for this work

Research output: Contribution to Journal › Review article › Academic › peer-review

382 Downloads (Pure)

Abstract

Transactive response DNA-binding protein 43 kDa (TDP-43), a multifunctional nucleic acid-binding protein, is a primary component of insoluble aggregates associated with several devastating nervous system disorders; mutations in TARDBP, its encoding gene, are a cause of familial amyotrophic lateral sclerosis (ALS) and frontotemporal dementia (FTD). Here, we review established and emerging roles of TDP-43 and consider how its dysfunction impinges on RNA homeostasis in the nervous system, thereby contributing to neural degeneration. Notably, improper splicing of the axonal growth-associated factor STMN2 has recently been connected to TDP-43 dysfunction, providing a mechanistic link between TDP-43 proteinopathies and neuropathy. This review highlights how a deep understanding of the function of TDP-43 in the brain might be leveraged to develop new targeted therapies for several neurological disorders.

Original language	English
Pages (from-to)	424-440
Number of pages	17
Journal	Trends in Neurosciences
Volume	44
Issue number	6
Early online date	5 Apr 2021
DOIs	https://doi.org/10.1016/j.tins.2021.02.008
Publication status	Published - Jun 2021

Bibliographical note

Funding Information:
J.R.K. was supported by the Tom Kirchhoff Family Postdoctoral Fellowship from Project ALS, L.A.N. is supported by the Healey Scholars postdoctoral fellowship, I.G.S.J. is supported by Target ALS, and K.E. is supported by the US National Institutes of Health (R01 grant NS089742). J.R.K. is an employee of Faze Medicines and a shareholder in Faze Medicines and QurAlis. K.E. and J.R.K. are authors on a pending patent that describes methods and compositions for restoring STMN2 levels surfaces (WO/2020/150290). K.E. is a founder of Q-State Biosciences, QurAlis, and EnClear Therapies, and currently employed at BioMarin Pharmaceutical. K.E. is an author on a pending patent that describes compounds and methods for treating neurodegenerative diseases (WO2020107037).

Funding Information:
J.R.K. was supported by the Tom Kirchhoff Family Postdoctoral Fellowship from Project ALS, L.A.N. is supported by the Healey Scholars postdoctoral fellowship, I.G.S.J. is supported by Target ALS , and K.E. is supported by the US National Institutes of Health (R01 grant NS089742 ).

Publisher Copyright:
© 2021 Elsevier Ltd

Copyright:
Copyright 2021 Elsevier B.V., All rights reserved.

Funding

J.R.K. was supported by the Tom Kirchhoff Family Postdoctoral Fellowship from Project ALS, L.A.N. is supported by the Healey Scholars postdoctoral fellowship, I.G.S.J. is supported by Target ALS, and K.E. is supported by the US National Institutes of Health (R01 grant NS089742). J.R.K. is an employee of Faze Medicines and a shareholder in Faze Medicines and QurAlis. K.E. and J.R.K. are authors on a pending patent that describes methods and compositions for restoring STMN2 levels surfaces (WO/2020/150290). K.E. is a founder of Q-State Biosciences, QurAlis, and EnClear Therapies, and currently employed at BioMarin Pharmaceutical. K.E. is an author on a pending patent that describes compounds and methods for treating neurodegenerative diseases (WO2020107037). J.R.K. was supported by the Tom Kirchhoff Family Postdoctoral Fellowship from Project ALS, L.A.N. is supported by the Healey Scholars postdoctoral fellowship, I.G.S.J. is supported by Target ALS , and K.E. is supported by the US National Institutes of Health (R01 grant NS089742 ).

Keywords

amyotrophic lateral sclerosis (ALS)
frontotemporal dementia (FTD)
motor neuron disease
RNA binding protein
SCG10
Stathmin2

UN SDGs

This output contributes to the following UN Sustainable Development Goals (SDGs)

Access to Document

10.1016/j.tins.2021.02.008

Connecting TDP-43 Pathology with NeuropathyFinal published version, 2.05 MBLicence: Article 25fa Dutch Copyright Act

Persistent URL (handle)

Persistent link

Cite this

@article{f761e05e37b3487cb66ee3aa933e3ac9,

title = "Connecting TDP-43 Pathology with Neuropathy",

abstract = "Transactive response DNA-binding protein 43 kDa (TDP-43), a multifunctional nucleic acid-binding protein, is a primary component of insoluble aggregates associated with several devastating nervous system disorders; mutations in TARDBP, its encoding gene, are a cause of familial amyotrophic lateral sclerosis (ALS) and frontotemporal dementia (FTD). Here, we review established and emerging roles of TDP-43 and consider how its dysfunction impinges on RNA homeostasis in the nervous system, thereby contributing to neural degeneration. Notably, improper splicing of the axonal growth-associated factor STMN2 has recently been connected to TDP-43 dysfunction, providing a mechanistic link between TDP-43 proteinopathies and neuropathy. This review highlights how a deep understanding of the function of TDP-43 in the brain might be leveraged to develop new targeted therapies for several neurological disorders.",

keywords = "amyotrophic lateral sclerosis (ALS), frontotemporal dementia (FTD), motor neuron disease, RNA binding protein, SCG10, Stathmin2",

author = "Klim, {Joseph R.} and Greta Pintacuda and Nash, {Leslie A.} and {Guerra San Juan}, Irune and Kevin Eggan",

note = "Funding Information: J.R.K. was supported by the Tom Kirchhoff Family Postdoctoral Fellowship from Project ALS, L.A.N. is supported by the Healey Scholars postdoctoral fellowship, I.G.S.J. is supported by Target ALS, and K.E. is supported by the US National Institutes of Health (R01 grant NS089742). J.R.K. is an employee of Faze Medicines and a shareholder in Faze Medicines and QurAlis. K.E. and J.R.K. are authors on a pending patent that describes methods and compositions for restoring STMN2 levels surfaces (WO/2020/150290). K.E. is a founder of Q-State Biosciences, QurAlis, and EnClear Therapies, and currently employed at BioMarin Pharmaceutical. K.E. is an author on a pending patent that describes compounds and methods for treating neurodegenerative diseases (WO2020107037). Funding Information: J.R.K. was supported by the Tom Kirchhoff Family Postdoctoral Fellowship from Project ALS, L.A.N. is supported by the Healey Scholars postdoctoral fellowship, I.G.S.J. is supported by Target ALS , and K.E. is supported by the US National Institutes of Health (R01 grant NS089742 ). Publisher Copyright: {\textcopyright} 2021 Elsevier Ltd Copyright: Copyright 2021 Elsevier B.V., All rights reserved.",

year = "2021",

month = jun,

doi = "10.1016/j.tins.2021.02.008",

language = "English",

volume = "44",

pages = "424--440",

journal = "Trends in Neurosciences",

issn = "0166-2236",

publisher = "Elsevier Ltd",

number = "6",

}

TY - JOUR

T1 - Connecting TDP-43 Pathology with Neuropathy

AU - Klim, Joseph R.

AU - Pintacuda, Greta

AU - Nash, Leslie A.

AU - Guerra San Juan, Irune

AU - Eggan, Kevin

N1 - Funding Information: J.R.K. was supported by the Tom Kirchhoff Family Postdoctoral Fellowship from Project ALS, L.A.N. is supported by the Healey Scholars postdoctoral fellowship, I.G.S.J. is supported by Target ALS, and K.E. is supported by the US National Institutes of Health (R01 grant NS089742). J.R.K. is an employee of Faze Medicines and a shareholder in Faze Medicines and QurAlis. K.E. and J.R.K. are authors on a pending patent that describes methods and compositions for restoring STMN2 levels surfaces (WO/2020/150290). K.E. is a founder of Q-State Biosciences, QurAlis, and EnClear Therapies, and currently employed at BioMarin Pharmaceutical. K.E. is an author on a pending patent that describes compounds and methods for treating neurodegenerative diseases (WO2020107037). Funding Information: J.R.K. was supported by the Tom Kirchhoff Family Postdoctoral Fellowship from Project ALS, L.A.N. is supported by the Healey Scholars postdoctoral fellowship, I.G.S.J. is supported by Target ALS , and K.E. is supported by the US National Institutes of Health (R01 grant NS089742 ). Publisher Copyright: © 2021 Elsevier Ltd Copyright: Copyright 2021 Elsevier B.V., All rights reserved.

PY - 2021/6

Y1 - 2021/6

N2 - Transactive response DNA-binding protein 43 kDa (TDP-43), a multifunctional nucleic acid-binding protein, is a primary component of insoluble aggregates associated with several devastating nervous system disorders; mutations in TARDBP, its encoding gene, are a cause of familial amyotrophic lateral sclerosis (ALS) and frontotemporal dementia (FTD). Here, we review established and emerging roles of TDP-43 and consider how its dysfunction impinges on RNA homeostasis in the nervous system, thereby contributing to neural degeneration. Notably, improper splicing of the axonal growth-associated factor STMN2 has recently been connected to TDP-43 dysfunction, providing a mechanistic link between TDP-43 proteinopathies and neuropathy. This review highlights how a deep understanding of the function of TDP-43 in the brain might be leveraged to develop new targeted therapies for several neurological disorders.

AB - Transactive response DNA-binding protein 43 kDa (TDP-43), a multifunctional nucleic acid-binding protein, is a primary component of insoluble aggregates associated with several devastating nervous system disorders; mutations in TARDBP, its encoding gene, are a cause of familial amyotrophic lateral sclerosis (ALS) and frontotemporal dementia (FTD). Here, we review established and emerging roles of TDP-43 and consider how its dysfunction impinges on RNA homeostasis in the nervous system, thereby contributing to neural degeneration. Notably, improper splicing of the axonal growth-associated factor STMN2 has recently been connected to TDP-43 dysfunction, providing a mechanistic link between TDP-43 proteinopathies and neuropathy. This review highlights how a deep understanding of the function of TDP-43 in the brain might be leveraged to develop new targeted therapies for several neurological disorders.

KW - amyotrophic lateral sclerosis (ALS)

KW - frontotemporal dementia (FTD)

KW - motor neuron disease

KW - RNA binding protein

KW - SCG10

KW - Stathmin2

UR - http://www.scopus.com/inward/record.url?scp=85103730693&partnerID=8YFLogxK

UR - http://www.scopus.com/inward/citedby.url?scp=85103730693&partnerID=8YFLogxK

U2 - 10.1016/j.tins.2021.02.008

DO - 10.1016/j.tins.2021.02.008

M3 - Review article

C2 - 33832769

AN - SCOPUS:85103730693

SN - 0166-2236

VL - 44

SP - 424

EP - 440

JO - Trends in Neurosciences

JF - Trends in Neurosciences

IS - 6

ER -

Connecting TDP-43 Pathology with Neuropathy

Abstract

Bibliographical note

Funding

Keywords

UN SDGs

Access to Document

Persistent URL (handle)

Other files and links

Fingerprint

Cite this