Phenotypic Suppression of ALS/FTD-Associated Neurodegeneration Highlights Mechanisms of Dysfunction

Bartoletti, Mathieu; Bosco, Daryl A.; Cruz, Sandrine Da; Lagier‐Tourenne, Clotilde; Liachko, Nicole F.; Markmiller, Sebastian; Webster, Kristin; Wharton, Kristi A.

doi:10.1523/jneurosci.1159-19.2019

Cited by 16 publications

(10 citation statements)

References 100 publications

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“…Familial cases of ALS are linked with mutations in one of > 25 different genes that act in a variety of cellular processes. A handful of genes harbor the majority of familial ALS mutations, including SOD1 , TDP-43, FUS and C9orf72 (Bartoletti et al 2019 ). Familial ALS-related mutations in TDP-43 and FUS proteins induce their cytosolic aggregation (Bentmann et al 2013 ; Liu-Yesucevitz et al 2010 ).…”

Section: Diseases Triggered By Protein Misfolding and Aggregationmentioning

confidence: 99%

Protein clearance strategies for disease intervention

Hommen

Bilican

2021

J Neural Transm

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Protein homeostasis, or proteostasis, is essential for cell function and viability. Unwanted, damaged, misfolded and aggregated proteins are degraded by the ubiquitin–proteasome system (UPS) and the autophagy-lysosome pathway. Growing evidence indicates that alterations in these major proteolytic mechanisms lead to a demise in proteostasis, contributing to the onset and development of distinct diseases. Indeed, dysregulation of the UPS or autophagy is linked to several neurodegenerative, infectious and inflammatory disorders as well as cancer. Thus, modulation of protein clearance pathways is a promising approach for therapeutics. In this review, we discuss recent findings and open questions on how targeting proteolytic mechanisms could be applied for disease intervention.

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Section: Diseases Triggered By Protein Misfolding and Aggregationmentioning

confidence: 99%

Protein clearance strategies for disease intervention

Hommen

Bilican

2021

J Neural Transm

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“…Approximately 90% of ALS cases are identified as sporadic (SALS), while ~10% are familial (FALS). In addition to motor dysfunction, up to 50% of ALS patients may also develop cognitive impairments and behavioral deficiencies, and among them, 15–20% are diagnosed with another neurodegenerative disorder, frontotemporal dementia (FTD), one of the most common types of dementia in people under 65 (Zago et al, 2011 ; Bartoletti et al, 2019 ; Abramzon et al, 2020 ). Similarly, up to 30% of FTD patients can develop motor dysfunction (Abramzon et al, 2020 ).…”

Section: Introductionmentioning

confidence: 99%

DNA Damage and Repair Deficiency in ALS/FTD-Associated Neurodegeneration: From Molecular Mechanisms to Therapeutic Implication

Wang

Manohar

Britz

et al. 2021

Front. Mol. Neurosci.

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Emerging studies reveal that neurodegenerative disorders, including amyotrophic lateral sclerosis (ALS) and frontotemporal dementia (FTD), are commonly linked to DNA damage accumulation and repair deficiency. Neurons are particularly vulnerable to DNA damage due to their high metabolic activity, relying primarily on oxidative phosphorylation, which leads to increased reactive oxygen species (ROS) generation and subsequent DNA damage. Efficient and timely repair of such damage is critical for guarding the integrity of genomic DNA and for cell survival. Several genes predominantly associated with RNA/DNA metabolism have been implicated in both ALS and FTD, suggesting that the two diseases share a common underlying pathology with varied clinical manifestations. Recent studies reveal that many of the gene products, including RNA/DNA binding proteins (RBPs) TDP-43 and FUS are involved in diverse DNA repair pathways. A key question in the etiology of the ALS/FTD spectrum of neurodegeneration is the mechanisms and pathways involved in genome instability caused by dysfunctions/mutations of those RBP genes and their consequences in the central nervous system. The understanding of such converging molecular mechanisms provides insights into the underlying etiology of the rapidly progressing neurodegeneration in ALS/FTD, while also revealing novel DNA repair target avenues for therapeutic development. In this review, we summarize the common mechanisms of neurodegeneration in ALS and FTD, with a particular emphasis on the DNA repair defects induced by ALS/FTD causative genes. We also highlight the consequences of DNA repair defects in ALS/FTD and the therapeutic potential of DNA damage repair-targeted amelioration of neurodegeneration.

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“…Identification of FALS-linked genes has informed on the biological mechanism(s) underlying ALS pathogenesis. The ∼25 known ALS proteins appear to cluster within three functional processes: cytoskeletal dynamics, protein homeostasis, and RNA processing (1,2). These categorizations are not mutually exclusive, however, in that some ALS-linked proteins can affect more than one process.…”

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confidence: 99%

ALS-linked PFN1 variants exhibit loss and gain of functions in the context of formin-induced actin polymerization

Schmidt

Funes

McKeon

et al. 2021

Proc. Natl. Acad. Sci. U.S.A.

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Profilin-1 (PFN1) plays important roles in modulating actin dynamics through binding both monomeric actin and proteins enriched with polyproline motifs. Mutations in PFN1 have been linked to the neurodegenerative disease amyotrophic lateral sclerosis (ALS). However, whether ALS-linked mutations affect PFN1 function has remained unclear. To address this question, we employed an unbiased proteomics analysis in mammalian cells to identify proteins that differentially interact with mutant and wild-type (WT) PFN1. These studies uncovered differential binding between two ALS-linked PFN1 variants, G118V and M114T, and select formin proteins. Furthermore, both variants augmented formin-mediated actin assembly relative to PFN1 WT. Molecular dynamics simulations revealed mutation-induced changes in the internal dynamic couplings within an alpha helix of PFN1 that directly contacts both actin and polyproline, as well as structural fluctuations within the actin- and polyproline-binding regions of PFN1. These data indicate that ALS-PFN1 variants have the potential for heightened flexibility in the context of the ternary actin–PFN1–polyproline complex during actin assembly. Conversely, PFN1 C71G was more severely destabilized than the other PFN1 variants, resulting in reduced protein expression in both transfected and ALS patient lymphoblast cell lines. Moreover, this variant exhibited loss-of-function phenotypes in the context of actin assembly. Perturbations in actin dynamics and assembly can therefore result from ALS-linked mutations in PFN1. However, ALS-PFN1 variants may dysregulate actin polymerization through different mechanisms that depend upon the solubility and stability of the mutant protein.

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Phenotypic Suppression of ALS/FTD-Associated Neurodegeneration Highlights Mechanisms of Dysfunction

Cited by 16 publications

References 100 publications

Protein clearance strategies for disease intervention

Protein clearance strategies for disease intervention

DNA Damage and Repair Deficiency in ALS/FTD-Associated Neurodegeneration: From Molecular Mechanisms to Therapeutic Implication

ALS-linked PFN1 variants exhibit loss and gain of functions in the context of formin-induced actin polymerization

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