TDP-43 proteinopathies: a new wave of neurodegenerative diseases

Boer, Eva M. J. de; Orie, Viyanti K; Williams, Tim; Baker, Mark R.; Oliveira, Hugo M De; Polvikoski, Tuomo; Silsby, Matthew; Menon, Parvathi; Bos, Mehdi van den; Halliday, Glenda M.; Berg, Leonard H van den; Bosch, Ludo Van Den; Damme, Philip Van; Kiernan, Matthew C.; Es, Michael A. van; Vucic, Steve

doi:10.1136/jnnp-2020-322983

Cited by 235 publications

(208 citation statements)

References 99 publications

Supporting

Mentioning

168

Contrasting

Unclassified

Order By: Relevance

“…The other two main genes causing familial forms of FTD, which overall represent up to a third of all FTD cases, are GRN and MAPT , associated, respectively, with FTLD-TDP and FTLD-tau ( Convery et al, 2019 ). ALS and FTD due to FTLD-TDP are now most commonly considered as two diseases belonging to the same neuropathological spectrum of TDP-43 proteinopathies ( de Boer et al, 2020 ). A further, far less common, neuropathological link between ALS and FTD is represented by FUS pathology, occurring in rare instances of both diseases; however, notably, whereas cases of ALS with FUS pathology are associated with mutations in the corresponding gene FUS , the vast majority of FTLD-FUS cases appear to be sporadic ( Mann and Snowden, 2017 ).…”

Section: Introductionmentioning

confidence: 99%

Neurofilament Light Chain as Biomarker for Amyotrophic Lateral Sclerosis and Frontotemporal Dementia

2021

View full text Add to dashboard Cite

Amyotrophic lateral sclerosis (ALS) and frontotemporal dementia (FTD) are two related currently incurable neurodegenerative diseases. ALS is characterized by degeneration of upper and lower motor neurons causing relentless paralysis of voluntary muscles, whereas in FTD, progressive atrophy of the frontal and temporal lobes of the brain results in deterioration of cognitive functions, language, personality, and behavior. In contrast to Alzheimer’s disease (AD), ALS and FTD still lack a specific neurochemical biomarker reflecting neuropathology ex vivo. However, in the past 10 years, considerable progress has been made in the characterization of neurofilament light chain (NFL) as cerebrospinal fluid (CSF) and blood biomarker for both diseases. NFL is a structural component of the axonal cytoskeleton and is released into the CSF as a consequence of axonal damage or degeneration, thus behaving in general as a relatively non-specific marker of neuroaxonal pathology. However, in ALS, the elevation of its CSF levels exceeds that observed in most other neurological diseases, making it useful for the discrimination from mimic conditions and potentially worthy of consideration for introduction into diagnostic criteria. Moreover, NFL correlates with disease progression rate and is negatively associated with survival, thus providing prognostic information. In FTD patients, CSF NFL is elevated compared with healthy individuals and, to a lesser extent, patients with other forms of dementia, but the latter difference is not sufficient to enable a satisfying diagnostic performance at individual patient level. However, also in FTD, CSF NFL correlates with several measures of disease severity. Due to technological progress, NFL can now be quantified also in peripheral blood, where it is present at much lower concentrations compared with CSF, thus allowing less invasive sampling, scalability, and longitudinal measurements. The latter has promoted innovative studies demonstrating longitudinal kinetics of NFL in presymptomatic individuals harboring gene mutations causing ALS and FTD. Especially in ALS, NFL levels are generally stable over time, which, together with their correlation with progression rate, makes NFL an ideal pharmacodynamic biomarker for therapeutic trials. In this review, we illustrate the significance of NFL as biomarker for ALS and FTD and discuss unsolved issues and potential for future developments.

show abstract

Section: Introductionmentioning

confidence: 99%

Neurofilament Light Chain as Biomarker for Amyotrophic Lateral Sclerosis and Frontotemporal Dementia

2021

View full text Add to dashboard Cite

show abstract

“…TDP-43 proteinopathy is a prominent neuropathological feature in the ALS/FTD disease spectrum that is also seen in a wide range of neurodegenerative diseases, inherited and sporadic 4 . Neither the factors driving TDP-43 pathology nor its involvement in neurodegeneration have been defined yet.…”

Section: Discussionmentioning

confidence: 99%

“…Cytoplasmic mislocalization of TDP-43 and aggregation of its hyperphosphorylated, ubiquitinated and C-terminal fragmented forms are common histopathological hallmarks of the amyotrophic lateral sclerosis (ALS) and frontotemporal dementia (FTD) disease spectrum 4,5 . TDP-43 proteinopathy is observed in ~97% of ALS and ~50% of FTD patients, in brain and spinal cord, but also in peripheral blood mononuclear cells (PBMCs) 6,7 .…”

Section: Introductionmentioning

confidence: 99%

Defective cyclophilin A induces TDP-43 proteinopathy: implications for amyotrophic lateral sclerosis and frontotemporal dementia

Pasetto

Grassano

Pozzi

et al. 2020

Preprint

View full text Add to dashboard Cite

Frontotemporal dementia (FTD) is a common cause of early-onset dementia, characterized by frontotemporal lobar degeneration and considerable clinical, genetic and neuropathological heterogeneity. Several mouse models of FTD have been generated targeting genes with known pathogenic roles. However, each of these models recapitulates only certain aspects of the human disease. Cyclophilin A (PPIA) is a multifunctional protein abundantly expressed in the brain, with double-edged functions. Intracellularly, it is mainly protective as a foldase and molecular chaperone with scaffolding properties. Extracellularly, it behaves as a proinflammatory cytokine able to activate an aberrant inflammatory response. In a previous work, we found that PPIA governs TDP-43 functions and its deficiency exacerbates disease in a mouse model of ALS.Selective inhibition of extracellular PPIA rescued motor neurons and increased survival. To decipher PPIA's functions in the central nervous system, we planned a deep neuropathological and behavioral characterization of PPIA knock-out (PPIA-/-) mice throughout their lifespan. They develop a neurodegenerative disease that recapitulates key features of the behavioral variant of FTD associated with TDP-43 pathology. PPIA-/-mice present progressive hippocampal and cortex atrophy, with neuronal death and clear-cut TDP-43 pathology that include fragmentation, hyperphosphorylation, and cytoplasmic mislocalization/nuclear clearing. Mice exhibit increased disinhibition, defects in social behavior, but no memory and motor impairment. On a molecular level, our findings indicate that PPIA is involved in multiple genes and pathways that have a dominant protective effect in the brain, and is fundamental for TDP-43 function. Considering that an impaired interaction of TDP-43 with PPIA has been observed in ALS/FTD patients, the PPIA-/-mouse is a useful experimental model to investigate the mechanism at the basis of TDP-43 pathology and develop novel therapeutic approaches for ALS/FTD and possibly other TDP-43 proteinopathies.

show abstract

“…Atrophy of the anterior roots is the most informative finding upon macroscopic observations, whereas that of the primary motor cortex is usually mild ( Figure 1 ). TDP-43 pathology has been observed in 95% of sporadic ALS cases [ 11 , 12 ], followed far behind by fused-in-sarcoma (FUS) [ 13 , 14 ]. TDP-43 is mislocalized from the nucleus and aggregates in the cytoplasm of motor neurons in ALS patients ( Figure 2 ).…”

Section: Tdp-43 Pathology In Als and Ftldmentioning

confidence: 99%

Pathway from TDP-43-Related Pathology to Neuronal Dysfunction in Amyotrophic Lateral Sclerosis and Frontotemporal Lobar Degeneration

Riku

Seilhean

Duyckaerts

et al. 2021

IJMS

View full text Add to dashboard Cite

Transactivation response DNA binding protein 43 kDa (TDP-43) is known to be a pathologic protein in amyotrophic lateral sclerosis (ALS) and frontotemporal lobar degeneration (FTLD). TDP-43 is normally a nuclear protein, but affected neurons of ALS or FTLD patients exhibit mislocalization of nuclear TDP-43 and cytoplasmic inclusions. Basic studies have suggested gain-of-neurotoxicity of aggregated TDP-43 or loss-of-function of intrinsic, nuclear TDP-43. It has also been hypothesized that the aggregated TDP-43 functions as a propagation seed of TDP-43 pathology. However, a mechanistic discrepancy between the TDP-43 pathology and neuronal dysfunctions remains. This article aims to review the observations of TDP-43 pathology in autopsied ALS and FTLD patients and address pathways of neuronal dysfunction related to the neuropathological findings, focusing on impaired clearance of TDP-43 and synaptic alterations in TDP-43-related ALS and FTLD. The former may be relevant to intraneuronal aggregation of TDP-43 and exocytosis of propagation seeds, whereas the latter may be related to neuronal dysfunction induced by TDP-43 pathology. Successful strategies of disease-modifying therapy might arise from further investigation of these subcellular alterations.

show abstract

TDP-43 proteinopathies: a new wave of neurodegenerative diseases

Cited by 235 publications

References 99 publications

Neurofilament Light Chain as Biomarker for Amyotrophic Lateral Sclerosis and Frontotemporal Dementia

Neurofilament Light Chain as Biomarker for Amyotrophic Lateral Sclerosis and Frontotemporal Dementia

Defective cyclophilin A induces TDP-43 proteinopathy: implications for amyotrophic lateral sclerosis and frontotemporal dementia

Pathway from TDP-43-Related Pathology to Neuronal Dysfunction in Amyotrophic Lateral Sclerosis and Frontotemporal Lobar Degeneration

Contact Info

Product

Resources

About