TY - JOUR
T1 - Emerging Therapies and Novel Targets for TDP-43 Proteinopathy in ALS/FTD
AU - Hayes, Lindsey R.
AU - Kalab, Petr
N1 - Publisher Copyright:
© 2022, The American Society for Experimental NeuroTherapeutics, Inc.
PY - 2022/7
Y1 - 2022/7
N2 - Nuclear clearance and cytoplasmic mislocalization of the essential RNA binding protein, TDP-43, is a pathologic hallmark of amyotrophic lateral sclerosis, frontotemporal dementia, and related neurodegenerative disorders collectively termed “TDP-43 proteinopathies.” TDP-43 mislocalization causes neurodegeneration through both loss and gain of function mechanisms. Loss of TDP-43 nuclear RNA processing function destabilizes the transcriptome by multiple mechanisms including disruption of pre-mRNA splicing, the failure of repression of cryptic exons, and retrotransposon activation. The accumulation of cytoplasmic TDP-43, which is prone to aberrant liquid–liquid phase separation and aggregation, traps TDP-43 in the cytoplasm and disrupts a host of downstream processes including the trafficking of RNA granules, local translation within axons, and mitochondrial function. In this review, we will discuss the TDP-43 therapy development pipeline, beginning with therapies in current and upcoming clinical trials, which are primarily focused on accelerating the clearance of TDP-43 aggregates. Then, we will look ahead to emerging strategies from preclinical studies, first from high-throughput genetic and pharmacologic screens, and finally from mechanistic studies focused on the upstream cause(s) of TDP-43 disruption in ALS/FTD. These include modulation of stress granule dynamics, TDP-43 nucleocytoplasmic shuttling, RNA metabolism, and correction of aberrant splicing events.
AB - Nuclear clearance and cytoplasmic mislocalization of the essential RNA binding protein, TDP-43, is a pathologic hallmark of amyotrophic lateral sclerosis, frontotemporal dementia, and related neurodegenerative disorders collectively termed “TDP-43 proteinopathies.” TDP-43 mislocalization causes neurodegeneration through both loss and gain of function mechanisms. Loss of TDP-43 nuclear RNA processing function destabilizes the transcriptome by multiple mechanisms including disruption of pre-mRNA splicing, the failure of repression of cryptic exons, and retrotransposon activation. The accumulation of cytoplasmic TDP-43, which is prone to aberrant liquid–liquid phase separation and aggregation, traps TDP-43 in the cytoplasm and disrupts a host of downstream processes including the trafficking of RNA granules, local translation within axons, and mitochondrial function. In this review, we will discuss the TDP-43 therapy development pipeline, beginning with therapies in current and upcoming clinical trials, which are primarily focused on accelerating the clearance of TDP-43 aggregates. Then, we will look ahead to emerging strategies from preclinical studies, first from high-throughput genetic and pharmacologic screens, and finally from mechanistic studies focused on the upstream cause(s) of TDP-43 disruption in ALS/FTD. These include modulation of stress granule dynamics, TDP-43 nucleocytoplasmic shuttling, RNA metabolism, and correction of aberrant splicing events.
KW - Amyotrophic lateral sclerosis
KW - Autophagy
KW - Frontotemporal dementia
KW - RNA
KW - Stress granules
KW - TDP-43
UR - http://www.scopus.com/inward/record.url?scp=85134657681&partnerID=8YFLogxK
UR - http://www.scopus.com/inward/citedby.url?scp=85134657681&partnerID=8YFLogxK
U2 - 10.1007/s13311-022-01260-5
DO - 10.1007/s13311-022-01260-5
M3 - Review article
C2 - 35790708
AN - SCOPUS:85134657681
SN - 1933-7213
VL - 19
SP - 1061
EP - 1084
JO - Neurotherapeutics
JF - Neurotherapeutics
IS - 4
ER -