Lys-63-specific deubiquitinase BRCC36 enhances the sensitivity of multiple myeloma cells to lenalidomide by inhibiting lysosomal degradation of cereblon.

Multiple myeloma (MM) is the second most common hematological tumor in adults. Immunomodulatory drugs (IMiDs), such as thalidomide and lenalidomide (Len), are effective drugs for the treatment of multiple myeloma. Len can recruit IKZF1 and IKZF3 to cereblon (CRBN), a substrate receptor of the cullin 4-RING E3 ligase (CRL4), promote their ubiquitination and degradation, and finally inhibit the proliferation of myeloma cells.

Glucosylceramide accumulation in microglia triggers STING-dependent neuroinflammation and neurodegeneration in mice.

Mutations in the gene encoding the lysosomal enzyme glucocerebrosidase (GCase) are responsible for Gaucher disease (GD) and are considered the strongest genetic risk factor for Parkinson's disease (PD) and Lewy body dementia (LBD). GCase deficiency leads to extensive accumulation of glucosylceramides (GCs) in cells and contributes to the neuropathology of GD, PD, and LBD by triggering chronic neuroinflammation. Here, we investigated the mechanisms by which GC accumulation induces neuroinflammation.

Inhibition of EHMT1/2 rescues synaptic damage and motor impairment in a PD mouse model.

Epigenetic dysregulation that leads to alterations in gene expression and is suggested to be one of the key pathophysiological factors of Parkinson's disease (PD). Here, we found that α-synuclein preformed fibrils (PFFs) induced histone H3 dimethylation at lysine 9 (H3K9me2) and increased the euchromatic histone methyltransferases EHMT1 and EHMT2, which were accompanied by neuronal synaptic damage, including loss of synapses and diminished expression levels of synaptic-related proteins. Furthermore, the levels of H3K9me2 at promoters in genes that encode the synaptic-related proteins SNAP25, PSD95, Synapsin 1 and vGLUT1 were increased in primary neurons after PFF treatment, which suggests a linkage between H3K9 dimethylation and synaptic dysfunction.

Deficient chaperone-mediated autophagy facilitates LPS-induced microglial activation via regulation of the p300/NF-κB/NLRP3 pathway.

Neuroinflammation is a pathological change that is involved in the progression of Parkinson's disease. Dysfunction of chaperone-mediated autophagy (CMA) has proinflammatory effects. However, the mechanism by which CMA mediates inflammation and whether CMA affects microglia and microglia-mediated neuronal damage remain to be elucidated.

Disrupted phase behavior of FUS underlies poly-PR-induced DNA damage in amyotrophic lateral sclerosis.

GGGGCC (G4C2) hexanucleotide repeat expansion (HRE) in the first intron of the chromosome 9 open reading frame 72 (C9ORF72) gene is the most common genetic cause of amyotrophic lateral sclerosis (ALS) and frontotemporal dementia (FTD). Among the five dipeptide repeat proteins translated from G4C2 HRE, arginine-rich poly-PR (proline:arginine) is extremely toxic. However, the molecular mechanism responsible for poly-PR-induced cell toxicity remains incompletely understood.

Tet2 acts in the lateral habenula to regulate social preference in mice.

The lateral habenula (LHb) has been considered a moderator of social behaviors. However, it remains unknown how LHb regulates social interaction. Here, we show that the hydroxymethylase Tet2 is highly expressed in the LHb.

Loss of DJ-1 function contributes to Parkinson's disease pathogenesis in mice via RACK1-mediated PKC activation and MAO-B upregulation.

Parkinson's disease (PD) is a common neurodegenerative motor disorder characterized by a dramatic reduction in pars compacta of substantia nigra dopaminergic neurons and striatal dopamine (DA) levels. Mutations or deletions in the PARK7/DJ-1 gene are associated with an early-onset familial form of PD. DJ-1 protein prevents neurodegeneration via its regulation of oxidative stress and mitochondrial function as well as its roles in transcription and signal transduction.

Pazopanib alleviates neuroinflammation and protects dopaminergic neurons in LPS-stimulated mouse model by inhibiting MEK4-JNK-AP-1 pathway.

Parkinson's disease (PD) is a progressive neurodegenerative disease characterized by the loss of dopaminergic (DA) neurons and the accumulation of Lewy bodies (LB) in the substantia nigra (SN). Evidence shows that microglia-mediated neuroinflammation plays a key role in PD pathogenesis. Using TNF-α as an indicator for microglial activation, we established a cellular model to screen compounds that could inhibit neuroinflammation.

Association of Glial Activation and α-Synuclein Pathology in Parkinson's Disease.

The accumulation of pathological α-synuclein (α-syn) in the central nervous system and the progressive loss of dopaminergic neurons in the substantia nigra pars compacta are the neuropathological features of Parkinson's disease (PD). Recently, the findings of prion-like transmission of α-syn pathology have expanded our understanding of the region-specific distribution of α-syn in PD patients. Accumulating evidence suggests that α-syn aggregates are released from neurons and endocytosed by glial cells, which contributes to the clearance of α-syn.

Bioinformatics and network-based screening and discovery of potential molecular targets and small molecular drugs for breast cancer.

Accurate identification of molecular targets of disease plays an important role in diagnosis, prognosis, and therapies. Breast cancer (BC) is one of the most common malignant cancers in women worldwide. Thus, the objective of this study was to accurately identify a set of molecular targets and small molecular drugs that might be effective for BC diagnosis, prognosis, and therapies, by using existing bioinformatics and network-based approaches.

Inhibition of the PINK1-Parkin Pathway Enhances the Lethality of Sorafenib and Regorafenib in Hepatocellular Carcinoma.

Hepatocellular carcinoma (HCC) is one of the most common fatal malignancies and the main cause of cancer-related deaths. The multitarget tyrosine kinase inhibitors (TKIs) sorafenib and regorafenib are systemic therapeutic drugs approved for the treatment of HCC. Here, we found that sorafenib and regorafenib injured mitochondria by inducing mitochondrial Ca (mtCa) overload and mitochondrial permeability transition pore (mPTP) opening, resulting in mitochondria-mediated cell death, which was alleviated by cyclosporin A (CsA), an inhibitor of mPTP.

DJ-1 inhibits microglial activation and protects dopaminergic neurons in vitro and in vivo through interacting with microglial p65.

Parkinson's disease (PD), one of the most common neurodegenerative disorders, is characterized by progressive neurodegeneration of dopaminergic (DA) neurons in the substantia nigra pars compacta (SNpc). DJ-1 acts essential roles in neuronal protection and anti-neuroinflammatory response, and its loss of function is tightly associated with a familial recessive form of PD. However, the molecular mechanism of DJ-1 involved in neuroinflammation is largely unclear.

The Cross-Links of Endoplasmic Reticulum Stress, Autophagy, and Neurodegeneration in Parkinson's Disease.

Parkinson's disease (PD) is the most common neurodegenerative movement disorder, and it is characterized by the selective loss of dopaminergic (DA) neurons in the substantia nigra pars compacta (SNpc), as well as the presence of intracellular inclusions with α-synuclein as the main component in surviving DA neurons. Emerging evidence suggests that the imbalance of proteostasis is a key pathogenic factor for PD. Endoplasmic reticulum (ER) stress-induced unfolded protein response (UPR) and autophagy, two major pathways for maintaining proteostasis, play important roles in PD pathology and are considered as attractive therapeutic targets for PD treatment.

Joint Genome-Wide Association Analyses Identified 49 Novel Loci For Age at Natural Menopause.

Background: Age at natural menopause (ANM) is an important index for women's health. Either early or late ANM is associated with a series of adverse outcomes later in life. Despite being an inheritable trait, its genetic determinant has not yet been fully understood.

Mendelian Randomization Analysis Reveals Causal Effects of the Human Gut Microbiota on Abdominal Obesity.

Background: Although recent studies have revealed an association between the composition of the gut microbiota and obesity, whether specific gut microbiota cause obesity has not been determined.

Objectives: The aim of this study is to determine the causal relationship between specific gut microbiota and abdominal obesity. Based on genome-wide association study (GWAS) summary statistics, we performed a 2-sample Mendelian randomization (MR) analysis to evaluate whether the gut microbiota affects abdominal obesity.

Imbalance of Lysine Acetylation Contributes to the Pathogenesis of Parkinson's Disease.

Parkinson's disease (PD) is one of the most common neurodegenerative disorders. The neuropathological features of PD are selective and progressive loss of dopaminergic neurons in the substantia nigra pars compacta, deficiencies in striatal dopamine levels, and the presence of intracellular Lewy bodies. Interactions among aging and genetic and environmental factors are considered to underlie the common etiology of PD, which involves multiple changes in cellular processes.

Role of the C9ORF72 Gene in the Pathogenesis of Amyotrophic Lateral Sclerosis and Frontotemporal Dementia.

Since the discovery of the C9ORF72 gene in 2011, great advances have been achieved in its genetics and in identifying its role in disease models and pathological mechanisms; it is the most common genetic cause of amyotrophic lateral sclerosis (ALS) and frontotemporal dementia (FTD). ALS patients with C9ORF72 expansion show heterogeneous symptoms. Those who are C9ORF72 expansion carriers have shorter survival after disease onset than non-C9ORF72 expansion patients.

Dependence of PINK1 accumulation on mitochondrial redox system.

Accumulation of PINK1 on the outer mitochondrial membrane (OMM) is necessary for PINK-mediated mitophagy. The proton ionophores, like carbonyl cyanide m-chlorophenylhydrazone (CCCP) and carbonyl cyanide-4-(trifluoromethoxy)phenylhydrazone (FCCP), inhibit PINK1 import into mitochondrial matrix and induce PINK1 OMM accumulation. Here, we show that the CHCHD4/GFER disulfide relay system in the mitochondrial intermembrane space (IMS) is required for PINK1 stabilization when mitochondrial membrane potential is lost.

E3 ubiquitin ligase HRD1 modulates the circadian clock through regulation of BMAL1 stability.

Circadian rhythm serves an essential role in numerous physiological functions. Circadian oscillations are organized by circadian clock components at the molecular level. The precision of the circadian clock is controlled by transcriptional-translational negative feedback loops, as well as post-translational modifications of clock proteins, including ubiquitination; however, the influence of E3 ligases on clock protein ubiquitination requires further investigation.

α-Synuclein aggregation and transmission in Parkinson's disease: a link to mitochondria and lysosome.

The presence of intraneuronal Lewy bodies (LBs) and Lewy neurites (LNs) in the substantia nigra (SN) composed of aggregated α-synuclein (α-syn) has been recognized as a hallmark of pathological changes in Parkinson's disease (PD). Numerous studies have shown that aggregated α-syn is necessary for neurotoxicity. Meanwhile, the mitochondrial and lysosomal dysfunctions are associated with α-syn pathogenicity The hypothesis that α-syn transmission in the human brain contributes to the instigation and progression of PD has provided insights into PD pathology.

Autophagy and Polyglutamine Disease.

Polyglutamine (polyQ) disease is a type of fatal neurodegenerative disease caused by an expansion of CAG repeats in a specific gene, resulting in a protein with an abnormal polyQ fragment. The age of onset and the degree of pathological deterioration are related to the length of the polyQ fragment. At least 9 kinds of polyglutamine diseases have been discovered, including Huntington disease (HD), dentatorubral pallidoluysian atrophy (DRPLA), spinobulbar muscular atrophy (SBMA) and six spinocerebellar ataxia (SCA) such as SCA1, 2, 3, 6, 7 and 17 subtypes (Table 9.

Autophagy and Lysosome Storage Disorders.

Lysosomal storage disorders (LSDs) are one of the most common human genetic metabolic diseases caused by gene mutations. Up to now, more than 70 LSDs have been identified and mainly divided into five categories. LSDs are mainly caused by defects in the function of enzymes or lysosomal-related proteins in lysosomes, which causes progressive accumulation of undigested macromolecules within the cell and results in stress and dysfunction in cells, tissues and organs.

Motor dysfunction and neurodegeneration in a C9orf72 mouse line expressing poly-PR.

A GGGGCC hexanucleotide repeat expansion in intron 1 of chromosome 9 open reading frame 72 (C9ORF72) gene is the most common genetic cause of amyotrophic lateral sclerosis (ALS) and frontotemporal dementia. Repeat-associated non-ATG translation of dipeptide repeat proteins (DPRs) contributes to the neuropathological features of c9FTD/ALS. Among the five DPRs, arginine-rich poly-PR are reported to be the most toxic.