Frontotemporal Dementia, Where Do We Stand? A Narrative Review

International Journal of Molecular Sciences, Journal Year: 2023, Volume and Issue: 24(14), P. 11732 - 11732

Published: July 21, 2023

Frontotemporal dementia (FTD) is a neurodegenerative disease of growing interest, since it accounts for up to 10% middle-age-onset dementias and entails social, economic, emotional burden the patients caregivers. It characterised by (at least initially) selective degeneration frontal and/or temporal lobe, generally leading behavioural alterations, speech disorders, psychiatric symptoms. Despite recent advances, given its extreme heterogeneity, an overview that can bring together all data currently available still lacking. Here, we aim provide state art on pathogenesis this disease, starting with established findings integrating them more ones. In particular, advances in genetics field will be examined, assessing relation both clinical manifestations histopathological findings, as well considering link other diseases, such amyotrophic lateral sclerosis (ALS). Furthermore, current diagnostic criteria explored, including neuroimaging methods, nuclear medicine investigations, biomarkers biological fluids. Of note, promising information provided neurophysiological i.e., electroencephalography non-invasive brain stimulation techniques, concerning alterations networks neurotransmitter systems reviewed. Finally, experimental therapies considered.

Language: Английский

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TDP-43-stratified single-cell proteomics of postmortem human spinal motor neurons reveals protein dynamics in amyotrophic lateral sclerosis

Cell Reports, Journal Year: 2024, Volume and Issue: 43(1), P. 113636 - 113636

Published: Jan. 1, 2024

A limitation of conventional bulk-tissue proteome studies in amyotrophic lateral sclerosis (ALS) is the confounding motor neuron (MN) signals by admixed non-MN proteins. Here, we leverage laser capture microdissection and nanoPOTS single-cell mass spectrometry-based proteomics to query changes protein expression single MNs from postmortem ALS control tissues. In a follow-up analysis, examine impact stratification based on cytoplasmic transactive response DNA-binding 43 (TDP-43)+ inclusion pathology profiles 2,238 We report extensive overlap differentially abundant proteins identified with or without overt TDP-43 pathology, suggesting early sustained dysregulation cellular respiration, mRNA splicing, translation, vesicular transport ALS. Together, these data provide insights into proteome-level associated proteinopathy begin demonstrate utility pathology-stratified trace sample for understanding dynamics human neurologic diseases.

Language: Английский

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TMEM106B core deposition associates with TDP-43 pathology and is increased in risk SNP carriers for frontotemporal dementia

Science Translational Medicine, Journal Year: 2024, Volume and Issue: 16(730)

Published: Jan. 17, 2024

Genetic variation at the transmembrane protein 106B gene ( TMEM106B) has been linked to risk of frontotemporal lobar degeneration with TDP-43 inclusions (FTLD-TDP) through an unknown mechanism. We found that presence TMEM106B rs3173615 protective genotype was associated longer survival after symptom onset in a postmortem FTLD-TDP cohort, suggesting slower disease course. The seminal discovery filaments derived from is common feature aging and, across range neurodegenerative disorders, suggests genetic variants could modulate and progression modulating aggregation. To explore this possibility assess pathological relevance accumulation, we generated new antibody targeting filament core sequence. Analysis samples revealed allele higher accumulation patients FTLD-TDP. In contrast, minimal deposition detected carriers allele. Although abundance monomeric full-length unchanged, exhibited increase dimeric TMEM106B. Increased also enhanced dysfunction, interactome data suggested role for impaired RNA transport, local translation, endolysosomal function Overall, these findings suggest prevention central mechanism by which haplotype reduces slows progression.

Language: Английский

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TBK1, a prioritized drug repurposing target for amyotrophic lateral sclerosis: evidence from druggable genome Mendelian randomization and pharmacological verification in vitro

BMC Medicine, Journal Year: 2024, Volume and Issue: 22(1)

Published: March 5, 2024

Abstract Background There is a lack of effective therapeutic strategies for amyotrophic lateral sclerosis (ALS); therefore, drug repurposing might provide rapid approach to meet the urgent need treatment. Methods To identify targets associated with ALS, we conducted Mendelian randomization (MR) analysis and colocalization using cis-eQTL druggable gene ALS GWAS data collections determine annotated that exhibited significant associations ALS. By subsequent discovery coupled inclusion criteria selection, identified several candidates corresponding their have been genetically validated. The pharmacological assays were then further assess efficacy genetics-supported repurposed drugs potential therapy in various cellular models. Results Through MR analysis, genes blood, including TBK1 [OR 1.30, 95%CI (1.19, 1.42)], TNFSF12 1.36, 1.56)], GPX3 1.28, (1.15, 1.43)], TNFSF13 0.45, (0.32, 0.64)], CD68 0.38, (0.24, 0.58)]. Additionally, brain, RESP18 1.11, (1.07, 1.16)], 0.57, (0.48, 0.68)], GDF9 0.77, (0.67, 0.88)], PTPRN 0.17, (0.08, 0.34)]. Among them, , confirmed analysis. We five opportunities targeting namely fostamatinib (R788), amlexanox (AMX), BIIB-023, RG-7212, glutathione as drugs. R788 AMX prioritized due genetic supports, safety profiles, cost-effectiveness evaluation. Further revealed mitigated neuroinflammation cell models characterized by overly active cGAS/STING signaling was induced MSA-2 or ALS-related toxic proteins (TDP-43 SOD1), through inhibition phosphorylation. Conclusions Our analyses provided evidence supporting above opportunities, FDA-approved drug-R788 served inhibitors. studies validated treating specific subtypes

Language: Английский

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Mitochondrial Dysfunction in Neurodegenerative Diseases: Mechanisms and Corresponding Therapeutic Strategies

Biomedicines, Journal Year: 2025, Volume and Issue: 13(2), P. 327 - 327

Published: Jan. 31, 2025

Neurodegenerative disease (ND) refers to the progressive loss and morphological abnormalities of neurons in central nervous system (CNS) or peripheral (PNS). Examples neurodegenerative diseases include Alzheimer's (AD), Parkinson's (PD), amyotrophic lateral sclerosis (ALS). Recent studies have shown that mitochondria play a broad role cell signaling, immune response, metabolic regulation. For example, mitochondrial dysfunction is closely associated with onset progression variety diseases, including ND, cardiovascular diabetes, cancer. The energy metabolism, imbalance dynamics, abnormal mitophagy can lead homeostasis, which induce pathological reactions such as oxidative stress, apoptosis, inflammation, damage system, participate occurrence development degenerative AD, PD, ALS. In this paper, latest research progress subject detailed. mechanisms mitophagy-mediated ND are reviewed from perspectives β-amyloid (Aβ) accumulation, dopamine neuron damage, superoxide dismutase 1 (SOD1) mutation. Based on mechanism research, new ideas methods for treatment prevention proposed.

Language: Английский

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PolyQ-expanded ataxin-2 aggregation impairs cellular processing-body homeostasis via sequestering the RNA helicase DDX6

Journal of Biological Chemistry, Journal Year: 2024, Volume and Issue: 300(7), P. 107413 - 107413

Published: May 27, 2024

Ataxin-2 (Atx2) is a polyglutamine (polyQ) tract-containing RNA-binding protein, while its polyQ expansion may cause protein aggregation that implicated in the pathogenesis of neurodegenerative diseases such as spinocerebellar ataxia type 2 (SCA2). However, molecular mechanism underlying how Atx2 contributes to proteinopathies remains elusive. Here, we investigated influence on assembly and functionality cellular processing bodies (P-bodies) by using biochemical fluorescence imaging approaches. We have revealed polyQ-expanded (PQE) sequesters DEAD-box RNA helicase (DDX6), an essential component P-bodies, into aggregates or puncta via some sequences. The N-terminal like-Sm (LSm) domain (residues 82-184) C-terminal DDX6 are responsible for interaction specific sequestration. Moreover, sequestration aggravate pre-mRNA mis-splicing, interfere with releasing endoribonuclease MARF1 promotes mRNA decay translational repression. Rescuing level can recover P-bodies preventing targeted from degradation. This study provides line evidence P-body components impairment homeostasis dysregulating metabolism, which disease pathologies potential therapeutic target.

Language: Английский

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Phase separation and pathologic transitions of RNP condensates in neurons: implications for amyotrophic lateral sclerosis, frontotemporal dementia and other neurodegenerative disorders

Frontiers in Molecular Neuroscience, Journal Year: 2023, Volume and Issue: 16

Published: Sept. 1, 2023

Liquid–liquid phase separation results in the formation of dynamic biomolecular condensates, also known as membrane-less organelles, that allow for assembly functional compartments and higher order structures within cells. Multivalent, reversible interactions between RNA-binding proteins (RBPs), including FUS, TDP-43, hnRNPA1, and/or RNA (e.g., RBP-RBP, RBP-RNA, RNA-RNA), result ribonucleoprotein (RNP) which are critical processing, mRNA transport, stability, stress granule assembly, translation. Stress granules, neuronal transport processing bodies examples cytoplasmic RNP while nucleolus Cajal representative nuclear condensates. In neurons, condensates promote long-range local translation dendrites axon, essential spatiotemporal regulation gene expression, axonal integrity synaptic function. Mutations RBPs pathologic mislocalization aggregation hallmarks several neurodegenerative diseases, amyotrophic lateral sclerosis (ALS), frontotemporal dementia (FTD), Alzheimer’s disease. ALS/FTD-linked mutations alter strength reversibility multivalent with other RNAs, resulting aberrant transitions. These have detrimental consequences on localization, translation, ultimately lead to compromised function Pathogenic protein is dependent various factors, dynamically arrested may serve an initial nucleation step aggregate formation. Recent studies focused identifying mechanisms by neurons resolve transitioned prevent pathogenic inclusions/aggregates. The present review focuses disease-linked RBPs, physiological functions role transitions disease, particularly ALS/FTD. We examine cellular contribute resolution potential therapeutic approaches aberrantly at a molecular level.

Language: Английский

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Roadmap for C9ORF72 in Frontotemporal Dementia and Amyotrophic Lateral Sclerosis: Report on the C9ORF72 FTD/ALS Summit

Neurology and Therapy, Journal Year: 2023, Volume and Issue: 12(6), P. 1821 - 1843

Published: Oct. 17, 2023

A summit held March 2023 in Scottsdale, Arizona (USA) focused on the intronic hexanucleotide expansion C9ORF72 gene and its relevance frontotemporal dementia (FTD) amyotrophic lateral sclerosis (ALS; C9ORF72-FTD/ALS). The goal of this was to connect basic scientists, clinical researchers, drug developers, individuals affected by C9ORF72-FTD/ALS evaluate how collaborative efforts across FTD-ALS disease spectrum might break down existing silos. Presentations discussions covered recent discoveries mechanisms, availability biomarkers advances therapeutic development, trial design for prevention treatment asymptomatic pathological carriers. C9ORF72-associated repeat is an important locus both ALS FTD. may be characterized loss function protein toxic gain functions caused dipeptide (DPR) proteins RNA. strategies discussed at included use antisense oligonucleotides, adeno-associated virus (AAV)-mediated silencing delivery, engineered small molecules targeting RNA structures associated with expansion. Neurofilament light chain, DPR proteins, transactive response (TAR) DNA-binding 43 (TDP-43)–associated molecular changes were presented as biomarker candidates. Similarly, brain imaging modalities (i.e., magnetic resonance [MRI] positron emission tomography [PET]) measuring structural, functional, metabolic tools monitor C9ORF72-FTD/ALS, pre-symptomatic symptomatic stages. Finally, attendees evaluated current designs available FTD or patients concluded that therapeutics relevant FTD/ALS patients, such those specifically C9ORF72, need tested composite endpoints covering symptoms ALS. latter will require novel inclusive all patient subgroups spanning spectrum. Summit (USA). Some people who have a change one their genes; name C9ORF72. People carry genetic difference usually inherited it from parent. Researchers are improving understanding affects people, being made knowledge develop treatments dementia. In addition studying cellular mechanisms mutation leads dysfunction symptoms, large effort research community aimed developing measurements, called biomarkers, could enhance therapy development multiple ways. Examples include monitoring activity, identifying risk dementia, predicting which benefit particular treatment, showing has had biological effect. Markers identify healthy used test would start before person shows any hopefully delay even prevent onset.

Language: Английский

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Autophagy and neurodegeneration: Unraveling the role of C9ORF72 in the regulation of autophagy and its relationship to ALS-FTD pathology

Frontiers in Cellular Neuroscience, Journal Year: 2023, Volume and Issue: 17

Published: March 16, 2023

The proper functioning of the cell clearance machinery is critical for neuronal health within central nervous system (CNS). In normal physiological conditions, actively involved in elimination misfolded and toxic proteins throughout lifetime an organism. highly conserved regulated pathway autophagy one important processes preventing neutralizing pathogenic buildup that could eventually lead to development neurodegenerative diseases (NDs) such as Alzheimer's disease or Amyotrophic lateral sclerosis (ALS). most common genetic cause ALS frontotemporal dementia (FTD) a hexanucleotide expansion consisting GGGGCC (G4C2) repeats chromosome 9 open reading frame 72 gene (C9ORF72). These abnormally expanded have been implicated leading three main modes pathology: loss function C9ORF72 protein, generation RNA foci, production dipeptide repeat (DPRs). this review, we discuss role autophagy-lysosome (ALP), present recent research deciphering how dysfunction ALP synergizes with haploinsufficiency, which together gain mechanisms involving expansions DPRs, drive process. This review delves further into interactions RAB endosomal/lysosomal trafficking, their regulating various steps lysosomal pathways. Lastly, aims provide framework investigations C9ORF72-linked ALS-FTD well other diseases.

Language: Английский

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Poly(GR) interacts with key stress granule factors promoting its assembly into cytoplasmic inclusions

Cell Reports, Journal Year: 2023, Volume and Issue: 42(8), P. 112822 - 112822

Published: July 19, 2023

C9orf72 repeat expansions are the most common genetic cause of frontotemporal dementia (FTD) and amyotrophic lateral sclerosis (ALS). Poly(GR) proteins toxic to neurons by forming cytoplasmic inclusions that sequester RNA-binding including stress granule (SG) proteins. However, little is known factors governing poly(GR) inclusion formation. Here, we show infiltrates a finely tuned network protein-RNA interactions underpinning SG It interacts with G3BP1, key driver assembly protein found critical for Moreover, discovered N6-methyladenosine (m6A)-modified mRNAs m6A-binding YTHDF not only co-localize in brains c9FTD/ALS mouse models patients c9FTD, they promote formation via incorporation RNA into inclusions. Our findings thus suggest interrupting between G3BP1 or YTHDF1 decreasing altogether represent promising therapeutic strategies combat pathogenesis.

Language: Английский

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