Mitochondria-targeted oligomeric α-synuclein induces TOM40 degradation and mitochondrial dysfunction in Parkinson's disease and parkinsonism-dementia of Guam.

Mitochondrial dysfunction is a central aspect of Parkinson's disease (PD) pathology, yet the underlying mechanisms are not fully understood. This study investigates the link between α-Synuclein (α-Syn) pathology and the loss of translocase of the outer mitochondrial membrane 40 (TOM40), unraveling its implications for mitochondrial dysfunctions in neurons. We discovered that TOM40 protein depletion occurs in the brains of patients with Guam Parkinsonism-Dementia (Guam PD) and cultured neurons expressing α-Syn proteinopathy, notably, without corresponding changes in TOM40 mRNA levels.

A Commentary on Mitochondrial Dysfunction and Compromised DNA Repair in Neurodegeneration: The Emerging Role of FUS in ALS.

Mitochondrial dysfunction plays a pivotal role in the progression of neurodegenerative diseases such as amyotrophic lateral sclerosis (ALS), Alzheimer's, and Parkinson's disease. Recent discoveries have highlighted the involvement of DNA damage and repair processes, particularly mitochondrial DNA (mtDNA) damage, in these conditions. This commentary reflects on our recent findings, demonstrating the RNA/DNA binding protein fused in sarcoma (FUS)'s crucial role in maintaining mtDNA integrity through interactions with mitochondrial DNA ligase IIIα (mtLig3).

Selective Inhibition of Cytosolic PARylation via PARG99: A Targeted Approach for Mitigating FUS-associated Neurodegeneration.

Neurodegenerative diseases such as amyotrophic lateral sclerosis (ALS) are characterized by complex etiologies, often involving disruptions in functions of RNA/DNA binding proteins (RDBPs) such as FUS and TDP-43. The cytosolic mislocalization and aggregation of these proteins are linked to accumulation of unresolved stress granules (SGs), which exacerbate the disease progression. Poly-ADP-ribose polymerase (PARP)-mediated PARylation plays a critical role in this pathological cascade, making it a potential target for intervention.

Hemin-Induced Transient Senescence Via DNA Damage Response: A Neuroprotective Mechanism Against Ferroptosis in Intracerebral Hemorrhage.

Intracerebral hemorrhage (ICH) poses acute fatality and long-term neurological risks due to hemin and iron accumulation from hemoglobin breakdown. Our observation that hemin induces DNA double-strand breaks (DSBs), prompting a senescence-like phenotype in neurons, necessitating deeper exploration of cellular responses. Using experimental ICH models and human ICH patient tissue, we elucidate hemin-mediated DNA damage response (DDR) inducing transient senescence and delayed expression of heme oxygenase (HO-1).

Regulation of DNA damage response by RNA/DNA-binding proteins: Implications for neurological disorders and aging.

RNA-binding proteins (RBPs) are evolutionarily conserved across most forms of life, with an estimated 1500 RBPs in humans. Traditionally associated with post-transcriptional gene regulation, RBPs contribute to nearly every known aspect of RNA biology, including RNA splicing, transport, and decay. In recent years, an increasing subset of RBPs have been recognized for their DNA binding properties and involvement in DNA transactions.

TDP43 interacts with MLH1 and MSH6 proteins in a DNA damage-inducible manner.

Amyotrophic lateral sclerosis (ALS) is a fatal neurodegenerative disease that affects the motor neuron. One aspect of the neuropathology involved in ALS includes increased genomic damage and impaired DNA repair capability. The TAR-DNA binding protein 43 (TDP43) has been associated with both sporadic and familial forms of ALS, and is typically observed as cytosolic mislocalization of protein aggregates, termed TDP43 proteinopathy.

TDP43 Interacts with MLH1 and MSH6 Proteins in A DNA Damage-Inducible Manner.

Amyotrophic lateral sclerosis (ALS) is a fatal neurodegenerative disease that affects the motor neuron. One aspect of the neuropathology involved in ALS includes increased genomic damage and impaired DNA repair capability. The TAR-DNA binding protein 43 (TDP43) has been associated with both sporadic and familial forms of ALS, and is typically observed as cytosolic mislocalization of protein aggregates, termed TDP43 proteinopathy.

RNA/DNA Binding Protein TDP43 Regulates DNA Mismatch Repair Genes with Implications for Genome Stability.

TAR DNA-binding protein 43 (TDP43) is increasingly recognized for its involvement in neurodegenerative diseases, particularly amyotrophic lateral sclerosis (ALS) and frontotemporal dementia (FTD). TDP43 proteinopathy, characterized by dysregulated nuclear export and cytoplasmic aggregation, is present in most ALS/FTD cases and is associated with a loss of nuclear function and genomic instability in neurons. Building on prior evidence linking TDP43 pathology to DNA double-strand breaks (DSBs), this study identifies a novel regulatory role for TDP43 in the DNA mismatch repair (MMR) pathway.

Mitochondria-Targeted Oligomeric α-Synuclein Induces TOM40 Degradation and Mitochondrial Dysfunction in Parkinson's Disease and Parkinsonism-Dementia of Guam.

Mitochondrial dysfunction is a central aspect of Parkinson's disease (PD) pathology, yet the underlying mechanisms are not fully understood. This study investigates the link between α-Synuclein (α-Syn) pathology and the loss of translocase of the outer mitochondrial membrane 40 (TOM40), unraveling its implications for mitochondrial dysfunctions in neurons. We discovered that TOM40 protein depletion occurs in the brains of patients with Guam Parkinsonism Dementia (Guam PD) and cultured neurons expressing α-Syn proteinopathy, notably, without corresponding changes in TOM40 mRNA levels.

FUS unveiled in mitochondrial DNA repair and targeted ligase-1 expression rescues repair-defects in FUS-linked motor neuron disease.

This study establishes the physiological role of Fused in Sarcoma (FUS) in mitochondrial DNA (mtDNA) repair and highlights its implications to the pathogenesis of FUS-associated neurodegenerative diseases such as amyotrophic lateral sclerosis (ALS). Endogenous FUS interacts with and recruits mtDNA Ligase IIIα (mtLig3) to DNA damage sites within mitochondria, a relationship essential for maintaining mtDNA repair and integrity in healthy cells. Using ALS patient-derived FUS mutant cell lines, a transgenic mouse model, and human autopsy samples, we discovered that compromised FUS functionality hinders mtLig3's repair role, resulting in increased mtDNA damage and mutations.

Endogenous TDP-43 mislocalization in a novel knock-in mouse model reveals DNA repair impairment, inflammation, and neuronal senescence.

TDP-43 mislocalization and aggregation are key pathological features of motor neuron diseases (MND) including amyotrophic lateral sclerosis (ALS) and frontotemporal dementia (FTD). However, transgenic hTDP-43 WT or ΔNLS-overexpression animal models mainly capture late-stages TDP-43 proteinopathy, and do not provide a complete understanding of early motor neuron-specific pathology during pre-symptomatic phases. We have now addressed this shortcoming by generating a new endogenous knock-in (KI) mouse model using a combination of CRISPR/Cas9 and FLEX Cre-switch strategy for the conditional expression of a mislocalized Tdp-43ΔNLS variant of mouse Tdp-43.

lncRNA Sequencing Reveals Neurodegeneration-Associated FUS Mutations Alter Transcriptional Landscape of iPS Cells That Persists in Motor Neurons.

Fused-in sarcoma (FUS) gene mutations have been implicated in amyotrophic lateral sclerosis (ALS). This study aimed to investigate the impact of FUS mutations (R521H and P525L) on the transcriptome of induced pluripotent stem cells (iPSCs) and iPSC-derived motor neurons (iMNs). Using RNA sequencing (RNA Seq), we characterized differentially expressed genes (DEGs) and differentially expressed lncRNAs (DELs) and subsequently predicted lncRNA-mRNA target pairs (TAR pairs).

FUS Unveiled in Mitochondrial DNA Repair and Targeted Ligase-1 Expression Rescues Repair-Defects in FUS-Linked Neurodegeneration.

This study establishes the physiological role of Fused in Sarcoma (FUS) in mitochondrial DNA (mtDNA) repair and highlights its implications to the pathogenesis of FUS-associated neurodegenerative diseases such as Amyotrophic lateral sclerosis (ALS). Endogenous FUS interacts with and recruits mtDNA Ligase IIIα (mtLig3) to DNA damage sites within mitochondria, a relationship essential for maintaining mtDNA repair and integrity in healthy cells. Using ALS patient-derived FUS mutant cell lines, a transgenic mouse model, and human autopsy samples, we discovered that compromised FUS functionality hinders mtLig3's repair role, resulting in increased mtDNA damage and mutations.

lncRNA Sequencing Reveals Neurodegeneration-associated FUS Mutations Alter Transcriptional Landscape of iPS Cells That Persists In Motor Neurons.

() gene mutations have been implicated in amyotrophic lateral sclerosis (ALS). This study aimed to investigate the impact of FUS mutations (R521H and P525L) on the transcriptome of induced pluripotent stem cells (iPSCs) and iPSC-derived motor neurons (iMNs). Using RNA sequencing (RNA Seq), we characterized differentially expressed genes (DEGs), differentially expressed lncRNAs (DELs), and subsequently predicted lncRNA-mRNA target pairs (TAR pairs).

Human DNA polymerase η promotes RNA-templated error-free repair of DNA double-strand breaks.

A growing body of evidence indicates that RNA plays a critical role in orchestrating DNA double-strand break repair (DSBR). Recently, we showed that homologous nascent RNA can be used as a template for error-free repair of double-strand breaks (DSBs) in the transcribed genome and to restore the missing sequence at the break site via the transcription-coupled classical nonhomologous end-joining (TC-NHEJ) pathway. TC-NHEJ is a complex multistep process in which a reverse transcriptase (RT) is essential for synthesizing the DNA strand from template RNA.

SARS-CoV-2 and the central nervous system: Emerging insights into hemorrhage-associated neurological consequences and therapeutic considerations.

Coronavirus disease 2019 (COVID-19), caused by the Severe Acute Respiratory Syndrome Coronavirus 2 (SARS-CoV-2) continues to impact our lives by causing widespread illness and death and poses a threat due to the possibility of emerging strains. SARS-CoV-2 targets angiotensin-converting enzyme 2 (ACE2) before entering vital organs of the body, including the brain. Studies have shown systemic inflammation, cellular senescence, and viral toxicity-mediated multi-organ failure occur during infectious periods.

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

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.

The ubiquitin-binding domain of DNA polymerase η directly binds to DNA clamp PCNA and regulates translesion DNA synthesis.

DNA polymerase eta (Polη) is a unique translesion DNA synthesis (TLS) enzyme required for the error-free bypass of ultraviolet ray (UV)-induced cyclobutane pyrimidine dimers in DNA. Therefore, its deficiency confers cellular sensitivity to UV radiation and an increased rate of UV-induced mutagenesis. Polη possesses a ubiquitin-binding zinc finger (ubz) domain and a PCNA-interacting-protein (pip) motif in the carboxy-terminal region.

Interdomain connecting loop and J loop structures determine cross-species compatibility of PCNA.

Eukaryotic proliferating cell nuclear antigen (PCNA) plays an essential role in orchestrating the assembly of the replisome complex, stimulating processive DNA synthesis, and recruiting other regulatory proteins during the DNA damage response. PCNA and its binding partner network are relatively conserved in eukaryotes, and it exhibits extraordinary structural similarity across species. However, despite this structural similarity, the PCNA of a given species is rarely functional in heterologous systems.

USP11 mediates repair of DNA-protein cross-links by deubiquitinating SPRTN metalloprotease.

DNA-protein cross-links (DPCs) are toxic DNA lesions that interfere with DNA metabolic processes such as replication, transcription, and recombination. USP11 deubiquitinase participates in DNA repair, but the role of USP11 in DPC repair is not known. SPRTN is a replication-coupled DNA-dependent metalloprotease that cleaves proteins cross-linked to DNA to promote DPC repair.

Structural analyses of PCNA from the fungal pathogen Candida albicans identify three regions with species-specific conformations.

An assembly of multiprotein complexes achieves chromosomal DNA replication at the replication fork. In eukaryotes, proliferating cell nuclear antigen (PCNA) plays a vital role in the assembly of multiprotein complexes at the replication fork and is essential for cell viability. PCNA from several organisms, including Saccharomyces cerevisiae, has been structurally characterised.

Altered Mitochondrial Dynamics in Motor Neuron Disease: An Emerging Perspective.

Mitochondria plays privotal role in diverse pathways that regulate cellular function and survival, and have emerged as a prime focus in aging and age-associated motor neuron diseases (MNDs), such as amyotrophic lateral sclerosis (ALS) and frontotemporal dementia (FTD). Accumulating evidence suggests that many amyloidogenic proteins, including MND-associated RNA/DNA-binding proteins fused in sarcoma (FUS) and TAR DNA binding protein (TDP)-43, are strongly linked to mitochondrial dysfunction. Animal model and patient studies have highlighted changes in mitochondrial structure, plasticity, replication/copy number, mitochondrial DNA instability, and altered membrane potential in several subsets of MNDs, and these observations are consistent with the evidence of increased excitotoxicity, induction of reactive oxygen species, and activation of intrinsic apoptotic pathways.

RT PCR array screening reveals distinct perturbations in DNA damage response signaling in FUS-associated motor neuron disease.

Amyotrophic lateral sclerosis (ALS) is a degenerative motor neuron disease that has been linked to defective DNA repair. Many familial ALS patients harbor autosomal dominant mutations in the gene encoding the RNA/DNA binding protein 'fused in sarcoma' (FUS) commonly inducing its cytoplasmic mislocalization. Recent reports from our group and others demonstrate a role of FUS in maintaining genome integrity and the DNA damage response (DDR).

Virulence and pathogenicity of a Candida albicans mutant with reduced filamentation.

Deletion of DNA polymerase eta (Rad30/Polη) in pathogenic yeast Candida albicans is known to reduce filamentation induced by serum, ultraviolet, and cisplatin. Because nonfilamentous C. albicans is widely accepted as avirulent form, here we explored the virulence and pathogenicity of a rad30Δ strain of C.

Human DNA polymerase delta is a pentameric holoenzyme with a dimeric p12 subunit.

Human DNA polymerase delta (Polδ), a holoenzyme consisting of p125, p50, p68, and p12 subunits, plays an essential role in DNA replication, repair, and recombination. Herein, using multiple physicochemical and cellular approaches, we found that the p12 protein forms a dimer in solution. In vitro reconstitution and pull down of cellular Polδ by tagged p12 substantiate the pentameric nature of this critical holoenzyme.