Four germline POLH variants, including two found in skin tumors, impair DNA polymerase η function and cellular tolerance to UV radiation and cisplatin.

DNA polymerase (pol) η is vital for accurately replicating DNA opposite ultraviolet light (UV)-induced cyclobutane pyrimidine dimers and cisplatin-induced intrastrand purine crosslinks. While human POLH deficiency is linked to the disease xeroderma pigmentosum variant, the functional consequences of germline and somatic POLH variants remain largely unexplored. We characterized nine nonsynonymous POLH germline variants, five of which have also been found in various tumors.

Zinc finger protein 184 prevents α-synuclein preformed fibril-mediated neurodegeneration through the interleukin enhancer binding factor 3-microRNA-7 pathway.

Parkinson's disease (PD) is a neurodegenerative disorder characterized by a loss of dopaminergic neurons. Recent studies suggested the association of zinc finger protein 184 (ZNF184) with PD. However, the functional role of ZNF184 in PD pathogenesis remains unclear.

Preclinical studies and transcriptome analysis in a model of Parkinson's disease with dopaminergic ZNF746 expression.

Background: The parkin-interacting substrate (PARIS, also known as ZNF746) is a transcriptional repressor, whose accumulation and phosphorylation play central pathological roles in Parkinson's disease (PD). PARIS-induced transcriptional repression of PGC-1α or MDM4 contributes to mitochondrial dysfunction and p53-dependent neuron loss in PD. Despite the important role of PARIS in PD pathogenesis, unbiased transcriptomic profiles influenced by PARIS accumulation in dopaminergic neurons remain unexplored.

Upregulation of p52-ZER6 (ZNF398) increases reactive oxygen species by suppressing metallothionein-3 in neuronal cells.

ZNF398/ZER6 belongs to the Krüppel-associated box (KRAB) domain-containing zinc finger proteins (K-ZNFs), the largest family of transcriptional repressors in higher organisms. ZER6 exists in two isoforms, p52 and p71, generated through alternative splicing. Our investigation revealed that p71-ZER6 is abundantly expressed in the stomach, kidney, liver, heart, and brown adipose tissue, while p52-ZER6 is predominantly found in the stomach and brain.

PARIS undergoes liquid-liquid phase separation and poly(ADP-ribose)-mediated solidification.

ZNF746 was identified as parkin-interacting substrate (PARIS). Investigating its pathophysiological properties, we find that PARIS undergoes liquid-liquid phase separation (LLPS) and amorphous solid formation. The N-terminal low complexity domain 1 (LCD1) of PARIS is required for LLPS, whereas the C-terminal prion-like domain (PrLD) drives the transition from liquid to solid phase.

Farnesol prevents aging-related muscle weakness in mice through enhanced farnesylation of Parkin-interacting substrate.

Peroxisome proliferator-activated receptor-γ coactivator-1α (PGC-1α) is a master regulator of mitochondrial biogenesis. Reduced PGC-1α abundance is linked to skeletal muscle weakness in aging or pathological conditions, such as neurodegenerative diseases and diabetes; thus, elevating PGC-1α abundance might be a promising strategy to treat muscle aging. Here, we performed high-throughput screening and identified a natural compound, farnesol, as a potent inducer of PGC-1α.

Identification of Three Human POLH Germline Variants Defective in Complementing the UV- and Cisplatin-Sensitivity of POLH-Deficient Cells.

DNA polymerase (pol) η is responsible for error-free translesion DNA synthesis (TLS) opposite ultraviolet light (UV)-induced - cyclobutane thymine dimers (CTDs) and cisplatin-induced intrastrand guanine crosslinks. POLH deficiency causes one form of the skin cancer-prone disease xeroderma pigmentosum variant (XPV) and cisplatin sensitivity, but the functional impacts of its germline variants remain unclear. We evaluated the functional properties of eight human POLH germline in silico-predicted deleterious missense variants, using biochemical and cell-based assays.

S-nitrosylated PARIS Leads to the Sequestration of PGC-1α into Insoluble Deposits in Parkinson's Disease Model.

Neuronal accumulation of parkin-interacting substrate (PARIS), a transcriptional repressor of peroxisome proliferator-activated receptor gamma coactivator 1-alpha (PGC-1α), has been observed in Parkinson's disease (PD). Herein, we showed that PARIS can be S-nitrosylated at cysteine 265 (C265), and S-nitrosylated PARIS (SNO-PARIS) translocates to the insoluble fraction, leading to the sequestration of PGC-1α into insoluble deposits. The mislocalization of PGC-1α in the insoluble fraction was observed in S-nitrosocysteine-treated PARIS knockout (KO) cells overexpressing PARIS WT but not S-nitrosylation deficient C265S mutant, indicating that insolubility of PGC-1α is SNO-PARIS-dependent.

Loss of zinc-finger protein 212 leads to Purkinje cell death and locomotive abnormalities with phospholipase D3 downregulation.

Although Krüppel-associated box domain-containing zinc-finger proteins (K-ZNFs) may be associated with sophisticated gene regulation in higher organisms, the physiological functions of most K-ZNFs remain unknown. The Zfp212 protein was highly conserved in mammals and abundant in the brain; it was mainly expressed in the cerebellum (Cb). Zfp212 (mouse homolog of human ZNF212) knockout (Zfp212-KO) mice showed a reduction in survival rate compared to wild-type mice after 20 months of age.

Parkin interacting substrate phosphorylation by c-Abl drives dopaminergic neurodegeneration.

Aberrant activation of the non-receptor kinase c-Abl is implicated in the development of pathogenic hallmarks of Parkinson's disease, such as α-synuclein aggregation and progressive neuronal loss. c-Abl-mediated phosphorylation and inhibition of parkin ligase function lead to accumulation of parkin interacting substrate (PARIS) that mediates α-synuclein pathology-initiated dopaminergic neurodegeneration. Here we show that, in addition to PARIS accumulation, c-Abl phosphorylation of PARIS is required for PARIS-induced cytotoxicity.

PARIS farnesylation prevents neurodegeneration in models of Parkinson's disease.

Accumulation of the parkin-interacting substrate (PARIS; ), due to inactivation of parkin, contributes to Parkinson's disease (PD) through repression of peroxisome proliferator-activated receptor-γ coactivator-1α (PGC-1α; ) activity. Here, we identify farnesol as an inhibitor of PARIS. Farnesol promoted the farnesylation of PARIS, preventing its repression of PGC-1α via decreasing PARIS occupancy on the promoter.

α-Synuclein A53T Binds to Transcriptional Adapter 2-Alpha and Blocks Histone H3 Acetylation.

α-Synuclein (α-syn) is a hallmark amyloidogenic protein component of Lewy bodies in dopaminergic neurons affected by Parkinson's disease (PD). Despite the multi-faceted gene regulation of α-syn in the nucleus, the mechanism underlying α-syn crosstalk in chromatin remodeling in PD pathogenesis remains elusive. Here, we identified transcriptional adapter 2-alpha (TADA2a) as a novel binding partner of α-syn using the BioID system.

ZNF746/PARIS promotes the occurrence of hepatocellular carcinoma.

Hepatocellular carcinoma (HCC) is the most common primary liver cancer to cause liver cancer related deaths worldwide. Zinc finger protein 746 (ZNF746), initially identified as a Parkin-interacting substrate (PARIS), acts as a transcriptional repressor of peroxisome proliferator-activated receptor-γ coactivator-1α (PGC-1α) in Parkinson's disease. As recent studies reported that PARIS is associated with cancer onset, we investigated whether PARIS is associated with HCC.

Salivary Immunoglobulin Gamma-3 Chain C Is a Promising Noninvasive Biomarker for Systemic Lupus Erythematosus.

We aimed to characterize the salivary protein components and identify biomarkers in patients with systemic lupus erythematosus (SLE). A proteomic analysis using two-dimensional gel electrophoresis and mass spectrometry was performed to determine the alterations of salivary proteins between patients with SLE and healthy controls, and the concentrations of the candidate proteins were measured through Western blot analysis and the enzyme-linked immunosorbent assay. The 10 differentially expressed protein spots were immunoglobulin gamma-3 chain C region (IGHG3), immunoglobulin alpha-1 chain C region, protein S100A8, lactoferrin, leukemia-associated protein 7, and 8-oxoguanine DNA glycosylase.

Amyloid-like oligomerization of AIMP2 contributes to α-synuclein interaction and Lewy-like inclusion.

Lewy bodies are pathological protein inclusions present in the brain of patients with Parkinson's disease (PD). These inclusions consist mainly of α-synuclein with associated proteins, such as parkin and its substrate aminoacyl transfer RNA synthetase complex-interacting multifunctional protein-2 (AIMP2). Although AIMP2 has been suggested to be toxic to dopamine neurons, its roles in α-synuclein aggregation and PD pathogenesis are largely unknown.

Prevention of mitochondrial impairment by inhibition of protein phosphatase 1 activity in amyotrophic lateral sclerosis.

Amyotrophic lateral sclerosis (ALS) is a fatal neurodegenerative disease caused by progressive loss of motor neurons (MNs) and subsequent muscle weakness. These pathological features are associated with numerous cellular changes, including alteration in mitochondrial morphology and function. However, the molecular mechanisms associating mitochondrial structure with ALS pathology are poorly understood.

Deubiquitinase USP29 Governs MYBBP1A in the Brains of Parkinson's Disease Patients.

The inactivation of parkin by mutation or post-translational modification contributes to dopaminergic neuronal death in Parkinson's disease (PD). The substrates of parkin, FBP1 and AIMP2, are accumulated in the postmortem brains of PD patients, and it was recently suggested that these parkin substrates transcriptionally activate deubiquitinase . Herein, we newly identified 160 kDa myb-binding protein (MYBBP1A) as a novel substrate of USP29.

Roles of ErbB3-binding protein 1 (EBP1) in embryonic development and gene-silencing control.

ErbB3-binding protein 1 (EBP1) is implicated in diverse cellular functions, including apoptosis, cell proliferation, and differentiation. Here, by generating genetic inactivation of mice, we identified the physiological roles of EBP1 in vivo. Loss of in mice caused aberrant organogenesis, including brain malformation, and death between E13.

Inflammatory mediators resulting from transglutaminase 2 expressed in mast cells contribute to the development of Parkinson's disease in a mouse model.

This study aimed to investigate the role of transglutaminase 2 (TG2) expressed in mast cells in substantia nigra (SN) in Parkinson's disease (PD) model or human PD patients. C57BL/6 mice received 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP) by ip injection to induce PD. Bone marrow-derived mast cells (BMMCs) were adoptively transferred to TG2 knockout (KO or TG2) mice by iv injection 1 day before MPTP injection or stimulated by 1 methyl-4-phenylpyridinium (MMP).

Dysregulated phosphorylation of Rab GTPases by LRRK2 induces neurodegeneration.

Background: Mutations in leucine-rich repeat kinase 2 (LRRK2) are the most common cause of familial and sporadic Parkinson's disease (PD). Elevated kinase activity is associated with LRRK2 toxicity, but the substrates that mediate neurodegeneration remain poorly defined. Given the increasing evidence suggesting a role of LRRK2 in membrane and vesicle trafficking, here we systemically screened Rab GTPases, core regulators of vesicular dynamics, as potential substrates of LRRK2 and investigated the functional consequence of such phosphorylation in cells and in vivo.

Estrogen receptor activation contributes to RNF146 expression and neuroprotection in Parkinson's disease models.

RNF146 is an E3 ubiquitin ligase that specifically recognizes and polyubiquitinates poly (ADP-ribose) (PAR)-conjugated substrates for proteasomal degradation. RNF146 has been shown to be neuroprotective against PAR polymerase-1 (PARP1)-induced cell death during stroke. Here we report that RNF146 expression and RNF146 inducers can prevent cell death elicited by Parkinson's disease (PD)-associated and PARP1-activating stimuli.

PARIS reprograms glucose metabolism by HIF-1α induction in dopaminergic neurodegeneration.

Our previous study found that PARIS (ZNF746) transcriptionally suppressed transketolase (TKT), a key enzyme in pentose phosphate pathway (PPP) in the substantia nigra (SN) of AAV-PARIS injected mice. In this study, we revealed that PARIS overexpression reprogrammed glucose metabolic pathway, leading to the increment of glycolytic proteins along with TKT reduction in the SN of AAV-PARIS injected mice. Knock-down of TKT in differentiated SH-SY5Y cells led to an increase of glycolytic enzymes and decrease of PPP-related enzymes whereas overexpression of TKT restored PARIS-mediated glucose metabolic shift, suggesting that glucose metabolic alteration by PARIS is TKT-dependent.

CRISPR-Cas9 Mediated Telomere Removal Leads to Mitochondrial Stress and Protein Aggregation.

Aging is considered the major risk factor for neurodegenerative diseases including Parkinson's disease (PD). Telomere shortening is associated with cellular senescence. In this regard, pharmacological or genetic inhibition of telomerase activity has been used to model cellular aging.

Identification of transketolase as a target of PARIS in substantia nigra.

Recently, PARIS (ZNF746) is introduced as authentic substrate of parkin and transcriptionally represses PGC-1α by binding to insulin responsive sequences (IRSs) in the promoter of PGC-1α. The overexpression of PARIS selectively leads to the loss of dopaminergic neurons (DN) and mitochondrial abnormalities in the substantia nigra (SN) of Parkinson's disease (PD) models. To identify PARIS target molecules altered in SN region-specific manner, LC-MS/MS-based quantitative proteomic analysis is employed to investigate proteomic alteration in the cortex, striatum, and SN of AAV-PARIS injected mice.