GGC repeat expansion in NOTCH2NLC induces dysfunction in ribosome biogenesis and translation.

GGC repeat expansion in the 5' untranslated region (UTR) of NOTCH2NLC is associated with a broad spectrum of neurological disorders, especially neuronal intranuclear inclusion disease (NIID). Studies have found that GGC repeat expansion in NOTCH2NLC induces the formation of polyglycine (polyG)-containing protein, which is involved in the formation of neuronal intranuclear inclusions. However, the mechanism of neurotoxicity induced by NOTCH2NLC GGC repeats is unclear. Here, we used NIID patient-specific induced pluripotent stem cell (iPSC)-derived 3D cerebral organoids (3DCOs) and cellular models to investigate the pathophysiological mechanisms of NOTCH2NLC GGC repeat expansion. IPSC-derived 3DCOs and cellular models showed the deposition of polyG-containing intranuclear inclusions. The NOTCH2NLC GGC repeats could induce the upregulation of autophagic flux, enhance integrated stress response and activate EIF2α phosphorylation. Bulk RNA sequencing for iPSC-derived neurons and single-cell RNA sequencing (scRNA-seq) for iPSC-derived 3DCOs revealed that NOTCH2NLC GGC repeats may be associated with dysfunctions in ribosome biogenesis and translation. Moreover, NOTCH2NLC GGC repeats could induce the NPM1 nucleoplasm translocation, increase nucleolar stress, impair ribosome biogenesis and induce ribosomal RNA sequestration, suggesting dysfunction of membraneless organelles in the NIID cellular model. Dysfunctions in ribosome biogenesis and phosphorylated EIF2α and the resulting increase in the formation of G3BP1-positive stress granules may together lead to whole-cell translational inhibition, which may eventually cause cell death. Interestingly, scRNA-seq revealed that NOTCH2NLC GGC repeats may be associated with a significantly decreased proportion of immature neurons while 3DCOs were developing. Together, our results underscore the value of patient-specific iPSC-derived 3DCOs in investigating the mechanisms of polyG diseases, especially those caused by repeats in human-specific genes.

Clearance dysfunction of trans-barrier transport and lymphatic drainage in cerebral small vessel disease: Review and prospect.

Cerebral small vessel disease (CSVD) causes 20%-25% of stroke and contributes to 45% of dementia cases worldwide. However, since its early symptoms are inconclusive in addition to the complexity of the pathological basis, there is a rather limited effective therapies and interventions. Recently, accumulating evidence suggested that various brain-waste-clearance dysfunctions are closely related to the pathogenesis and prognosis of CSVD, and after a comprehensive and systematic review we classified them into two broad categories: trans-barrier transport and lymphatic drainage. The former includes blood brain barrier and blood-cerebrospinal fluid barrier, and the latter, glymphatic-meningeal lymphatic system and intramural periarterial drainage pathway. We summarized the concepts and potential mechanisms of these clearance systems, proposing a relatively complete framework for elucidating their interactions with CSVD. In addition, we also discussed recent advances in therapeutic strategies targeting clearance dysfunction, which may be an important area for future CSVD research.

Integrating single-nucleus sequence profiling to reveal the transcriptional dynamics of Alzheimer's disease, Parkinson's disease, and multiple sclerosis.

BACKGROUND: Alzheimer's disease (AD), Parkinson's disease (PD), and multiple sclerosis (MS) are three nervous system diseases that partially overlap clinically and genetically. However, bulk RNA-sequencing did not accurately detect the core pathogenic molecules in them. The availability of high-quality single cell RNA-sequencing data of post-mortem brain collections permits the generation of a large-scale gene expression in different cells in human brain, focusing on the molecular features and relationships between diseases and genes. We integrated single-nucleus RNA-sequencing (snRNA-seq) datasets of human brains with AD, PD, and MS to identify transcriptomic commonalities and distinctions among them. METHODS: The snRNA-seq datasets were downloaded from Gene Expression Omnibus (GEO) database. The Seurat package was used for snRNA-seq data processing. The uniform manifold approximation and projection (UMAP) were utilized for cluster identification. The FindMarker function in Seurat was used to identify the differently expressed genes. Functional enrichment analysis was carried out using the Gene Set Enrichment Analysis (GSEA) and Gene ontology (GO). The protein-protein interaction (PPI) analysis of differentially expressed genes (DEGs) was analyzed using STRING database ( http://string-db.org ). SCENIC analysis was performed using utilizing pySCENIC (v0.10.0) based on the hg19-tss-centered-10 kb-10species databases. The analysis of potential therapeutic drugs was analyzed on Connectivity Map ( https://clue.io ). RESULTS: The gene regulatory network analysis identified several hub genes regulated in AD, PD, and MS, in which HSPB1 and HSPA1A were key molecules. These upregulated HSP family genes interact with ribosome genes in AD and MS, and with immunomodulatory genes in PD. We further identified several transcriptional regulators (SPI1, CEBPA, TFE3, GRHPR, and TP53) of the hub genes, which has important implications for uncovering the molecular crosstalk among AD, PD, and MS. Arctigenin was identified as a potential therapeutic drug for AD, PD, and MS. CONCLUSIONS: Together, the integrated snRNA-seq data and findings have significant implications for unraveling the shared and unique molecular crosstalk among AD, PD, and MS. HSPB1 and HSPA1A as promising targets involved in the pathological mechanisms of neurodegenerative diseases. Additionally, the identification of arctigenin as a potential therapeutic drug for AD, PD, and MS further highlights its potential in treating these neurological disorders. These discoveries lay the groundwork for future research and interventions to enhance our understanding and treatment of AD, PD, and MS.

Physiological ß-amyloid clearance by the liver and its therapeutic potential for Alzheimer's disease.

Cerebral amyloid-ß (Aß) accumulation due to impaired Aß clearance is a pivotal event in the pathogenesis of Alzheimer's disease (AD). Considerable brain-derived Aß is cleared via transporting to the periphery. The liver is the largest organ responsible for the clearance of metabolites in the periphery. Whether the liver physiologically clears circulating Aß and its therapeutic potential for AD remains unclear. Here, we found that about 13.9% of Aß42 and 8.9% of Aß40 were removed from the blood when flowing through the liver, and this capacity was decreased with Aß receptor LRP-1 expression down-regulated in hepatocytes in the aged animals. Partial blockage of hepatic blood flow increased Aß levels in both blood and brain interstitial fluid. The chronic decline in hepatic Aß clearance via LRP-1 knockdown specific in hepatocytes aggravated cerebral Aß burden and cognitive deficits, while enhancing hepatic Aß clearance via LRP-1 overexpression attenuated cerebral Aß deposition and cognitive impairments in APP/PS1 mice. Our findings demonstrate that the liver physiologically clears blood Aß and regulates brain Aß levels, suggesting that a decline of hepatic Aß clearance during aging could be involved in AD development, and hepatic Aß clearance is a novel therapeutic approach for AD.

Shared Genetic Architecture between Parkinson's Disease and Brain Structural Phenotypes.

BACKGROUND: Patients with Parkinson's disease (PD) have consistently demonstrated brain structure abnormalities, indicating the presence of shared etiological and pathological processes between PD and brain structures; however, the genetic relationship remains poorly understood. OBJECTIVE: The aim of this study was to investigate the extent of shared genetic architecture between PD and brain structural phenotypes (BSPs) and to identify shared genomic loci. METHODS: We used the summary statistics from genome-wide association studies to conduct MiXeR and conditional/conjunctional false discovery rate analyses to investigate the shared genetic signatures between PD and BSPs. Subsequent expression quantitative trait loci mapping in the human brain and enrichment analyses were also performed. RESULTS: MiXeR analysis identified genetic overlap between PD and various BSPs, including total cortical surface area, average cortical thickness, and specific brain volumetric structures. Further analysis using conditional false discovery rate (FDR) identified 21 novel PD risk loci on associations with BSPs at conditional FDR < 0.01, and the conjunctional FDR analysis demonstrated that PD shared several genomic loci with certain BSPs at conjunctional FDR < 0.05. Among the shared loci, 16 credible mapped genes showed high expression in the brain tissues and were primarily associated with immune function-related biological processes. CONCLUSIONS: We confirmed the polygenic overlap with mixed directions of allelic effects between PD and BSPs and identified multiple shared genomic loci and risk genes, which are likely related to immune-related biological processes. These findings provide insight into the complex genetic architecture associated with PD. © 2023 International Parkinson and Movement Disorder Society.

Identifying causal genes for migraine by integrating the proteome and transcriptome.

BACKGROUND: While previous genome-wide association studies (GWAS) have identified multiple risk variants for migraine, there is a lack of evidence about how these variants contribute to the development of migraine. We employed an integrative pipeline to efficiently transform genetic associations to identify causal genes for migraine. METHODS: We conducted a proteome-wide association study (PWAS) by combining data from the migraine GWAS data with proteomic data from the human brain and plasma to identify proteins that may play a role in the risk of developing migraine. We also combined data from GWAS of migraine with a novel joint-tissue imputation (JTI) prediction model of 17 migraine-related human tissues to conduct transcriptome-wide association studies (TWAS) together with the fine mapping method FOCUS to identify disease-associated genes. RESULTS: We identified 13 genes in the human brain and plasma proteome that modulate migraine risk by regulating protein abundance. In addition, 62 associated genes not reported in previous migraine TWAS studies were identified by our analysis of migraine using TWAS and fine mapping. Five genes including ICA1L, TREX1, STAT6, UFL1, and B3GNT8 showed significant associations with migraine at both the proteome and transcriptome, these genes are mainly expressed in ependymal cells, neurons, and glial cells, and are potential target genes for prevention of neuronal signaling and inflammatory responses in the pathogenesis of migraine. CONCLUSIONS: Our proteomic and transcriptome findings have identified disease-associated genes that may give new insights into the pathogenesis and potential therapeutic targets for migraine.

Genetic analysis of the ATP11B gene in Chinese Han population with cerebral small vessel disease.

BACKGROUND: A loss-of-function mutation in ATPase phospholipid transporting 11-B (putative) (ATP11B) gene causing cerebral small vessel disease (SVD) in vivo, and a single intronic nucleotide polymorphism in ATP11B: rs148771930 that was associated with white matter hyperintensities burden in European patients with SVD, was recently identified. Our results suggest that ATP11B may not play an essential role in SVD in the Chinese population. RESULTS: We performed target region sequencing including ATP11B gene in 182 patients with sporadic SVD, and identified five rare variants and two novel variants of ATP11B. A case-control study was then performed in 524 patients and matched 550 controls to investigate the relationship between ATP11B and sporadic SVD in the Chinese Han population. Although none of these variants were significantly associated with SVD in our samples, it is important to mention that we identified a novel variant, p. G238W, which was predicted to be pathogenic in silico. This variant was present in our cohort of patients with an extremely low frequency and was absent in the controls. CONCLUSION: Our results suggest that ATP11B may not play an essential role in SVD in the Chinese population.

NOTCH2NLC Intermediate-Length Repeat Expansions Are Associated with Parkinson Disease.

NOTCH2NLC GGC repeat expansions were recently identified in neuronal intranuclear inclusion disease (NIID); however, it remains unclear whether they occur in other neurodegenerative disorders. This study aimed to investigate the role of intermediate-length NOTCH2NLC GGC repeat expansions in Parkinson disease (PD). We screened for GGC repeat expansions in a cohort of 1,011 PD patients and identified 11 patients with intermediate-length repeat expansions ranging from 41 to 52 repeats, with no repeat expansions in 1,134 controls. Skin biopsy revealed phospho-alpha-synuclein deposition, confirming the PD diagnosis in 2 patients harboring intermediate-length repeat expansions instead of NIID or essential tremor. Fibroblasts from PD patients harboring intermediate-length repeat expansions revealed NOTCH2NLC upregulation and autophagic dysfunction. Our results suggest that intermediate-length repeat expansions in NOTCH2NLC are potentially associated with PD. ANN NEUROL 2021;89:182-187.

Relapse factors of patients of anti-N-methyl-D-aspartate receptor encephalitis.

BACKGROUND: The factors associated with anti-N-methyl-D-aspartate (NMDA) receptor encephalitis relapse are yet to be elucidated. AIMS OF THE STUDY: To investigate the factors associated with relapse and prognosis of anti-NMDA receptor encephalitis. METHODS: This retrospective study included patients diagnosed with anti-NMDA receptor encephalitis admitted to the First Affiliated Hospital of Zhengzhou University from January 2013 to October 2019. The clinical features, auxiliary examinations, treatment regimens, and follow-up were recorded. The outcomes were relapse and 2-year disease prognosis. RESULTS: A total of 160 patients were included. Consequently, 6 (5%) deaths, 34 (25.4%) relapses, and 19 (15.2%) patients had a poor prognosis (modified Rankin score (mRS) ≥3) were recorded. The multivariable analyses showed that age (p = .011), abnormal magnetic resonance imaging (MRI) (p = .019), glucocorticoid pulse (p = .009), and intracranial pressure (p = .023) were independently associated with the relapse, while age (p = .030) and central hypoventilation (p = .020) were independently associated with a poor prognosis at 2 years. CONCLUSION: Glucocorticoid pulse therapy reduces the relapse of anti-NMDA receptor encephalitis. Age, abnormal MRI, and intracranial pressure are risk factors for relapse, while age and central hypoventilation are independently associated with poor prognosis.

Disrupted structure and aberrant function of CHIP mediates the loss of motor and cognitive function in preclinical models of SCAR16.

CHIP (carboxyl terminus of heat shock 70-interacting protein) has long been recognized as an active member of the cellular protein quality control system given the ability of CHIP to function as both a co-chaperone and ubiquitin ligase. We discovered a genetic disease, now known as spinocerebellar autosomal recessive 16 (SCAR16), resulting from a coding mutation that caused a loss of CHIP ubiquitin ligase function. The initial mutation describing SCAR16 was a missense mutation in the ubiquitin ligase domain of CHIP (p.T246M). Using multiple biophysical and cellular approaches, we demonstrated that T246M mutation results in structural disorganization and misfolding of the CHIP U-box domain, promoting oligomerization, and increased proteasome-dependent turnover. CHIP-T246M has no ligase activity, but maintains interactions with chaperones and chaperone-related functions. To establish preclinical models of SCAR16, we engineered T246M at the endogenous locus in both mice and rats. Animals homozygous for T246M had both cognitive and motor cerebellar dysfunction distinct from those observed in the CHIP null animal model, as well as deficits in learning and memory, reflective of the cognitive deficits reported in SCAR16 patients. We conclude that the T246M mutation is not equivalent to the total loss of CHIP, supporting the concept that disease-causing CHIP mutations have different biophysical and functional repercussions on CHIP function that may directly correlate to the spectrum of clinical phenotypes observed in SCAR16 patients. Our findings both further expand our basic understanding of CHIP biology and provide meaningful mechanistic insight underlying the molecular drivers of SCAR16 disease pathology, which may be used to inform the development of novel therapeutics for this devastating disease.

Association of CYP3A4*1G and CYP3A5*3 With the 1-year Outcome of Acute Ischemic Stroke in the Han Chinese Population.

BACKGROUND AND PURPOSE: Previous studies have shown that common variants within CYP3A4 and CYP3A5 are associated with statin pharmacokinetics and the risk of cardiovascular disease. However, the association of variants in CYP3A4 and CYP3A5 with the prognosis of ischemic stroke remains undetermined. Therefore, we investigated this herein. METHODS: Four hundred thirty-three consecutive patients with acute ischemic stroke were recruited. The outcome at the 1-year follow-up was assessed using the modified Rankin Scale (mRS). Two variants, CYP3A4*1G and CYP3A5*3, were genotyped by the improved Multiple Ligase Detection Reaction platform. RESULTS: Binary logistic regression analysis showed that the CYP3A4*1G/*1G homozygote was associated with poor outcome at 1 year (mRS score ≥2) after adjustment for conventional factors in the additive model (odds ratio [OR] = 2.92; 95% confidence interval, 1.07-7.98; P = .037) and recessive model (OR = 3.37; 95% confidence interval, 1.26-9.04; P = .016). Subgroup analysis indicated that the CYP3A4*1G/*1G homozygote was associated with poor prognosis at 1 year among patients with stable high-intensity atorvastatin therapy (40-80 mg/d) after adjustment for conventional factors in the additive model (OR = 8.16; 95% confidence interval, 1.50-44.44; P = .015) and recessive model (OR = 9.06; 95% confidence interval, 1.72-47.64; P = .009). No significant association was identified between CYP3A5*3 and the 1-year outcome of patients with ischemic stroke. CONCLUSIONS: Our study findings suggest that the CYP3A4*1G/CYP3A4*1G genotype may be associated with poor prognosis at 1 year after acute ischemic stroke in the Han Chinese population.

Nr4a1 plays a crucial modulatory role in Th1/Th17 cell responses and CNS autoimmunity.

Nuclear receptor4 group A1 (Nr4a1), an orphan nuclear receptor, is down-regulated in peripheral blood mononuclear cells (MNCs) of individuals with multiple sclerosis (MS), and Nr4a1 deficiency results in severe experimental autoimmune encephalomyelitis (EAE), an animal model of MS, caused by increased macrophage infiltration into the central nervous system (CNS). However, the role of Nr4a1 in macrophage phenotype and T cell responses remains poorly understood. In the present study we show that macrophages/microglia of Nr4a1-/- mice, which exhibited earlier onset and more severe clinical EAE, were polarized to an enhanced type 1 (M1) phenotype and produced higher levels of IL-12 and TNF-α than wild type mice. Significantly increased numbers of CD4+ T cells and frequency of CD4+IFN-γ+ and CD4+IL-17+ T cells were observed in the CNS and spleen of Nr4a1-/- mice, with decreased percentages of apoptosis in CD4+ T cells. The percentages of CD4+Foxp3+ Treg cells in the CNS of Nr4a1-/- mice were also reduced. Furthermore, purified CD4+ T cells from naïve Nr4a1-/- mice exhibited enhanced Th1 and Th17 differentiation capacity, and MOG-reactive Th17 cells from Nr4a1-/- mice adoptively transferred more severe EAE in recipient mice. Our results, for the first time, demonstrate that Nr4a1 not only induces Type 2 macrophages/microglia phenotype, but is also a critical inhibitory molecule for Th1/Th17 cell differentiation. This finding indicates that Nr4a1-related molecule(s) may have therapeutic potential in MS and likely other autoimmune disorders.

Papillary Thyroid Carcinoma Incidentally Found in Cervical Lymph Nodes During Neck Dissection for Patients With Tongue Squamous Cell Carcinoma: A 3-Case Report and Literature Review.

The incidence of papillary thyroid carcinoma (PTC) found in the cervical lymph nodes during neck dissection for patients with tongue squamous cell carcinoma (SCC) is infrequent, with the coexistence of PTC and SCC in the same cervical lymph node being the rarest. Some of these patients present with primary lesions in the thyroid gland, whereas others have no obviously malignant thyroid lesion. The reasons behind this clinical phenomenon and the relationship between tongue SCC and PTC found in the cervical lymph nodes are unclear. Moreover, for surgeons, making the choice between thyroid surgery and follow-up is still a clinical dilemma. Of the 956 patients who underwent neck dissection owing to maxillofacial tumors from January 2011 through December 2017 at Second Xiangya Hospital of Central South University, 3 with tongue SCC presented with PTC in the cervical lymph nodes. Neither the preoperative physical examination nor ultrasonography after surgery showed substantial nodules in the thyroid glands of these patients, so none of them underwent thyroid surgery or chemoradiotherapy. At follow-up (1 to 6.5 years), we found no obviously malignant lesions in the patients' thyroid glands or related metastatic disease. Our study suggests that tongue SCC may not affect the occurrence and development of PTC in the cervical lymph nodes. For patients with tongue SCC presenting with PTC in the cervical lymph nodes, it is not necessary to carry out thyroid surgery immediately if ultrasonography shows no substantially malignant lesion in the thyroid gland. Nevertheless, conducting periodic follow-up is very important.

Characteristics and Management of Free Flap Compromise Following Internal Jugular Venous Thrombosis.

PURPOSE: Free flap compromise after internal jugular venous thrombosis (IJVT) occurs fairly infrequently in oral and maxillofacial rehabilitation and reconstruction but could seriously affect the patient's postoperative recovery. The aim of this study was to analyze and discuss the characteristics and management of such flap compromise. PATIENTS AND METHODS: The authors performed a retrospective case series of 13 patients who underwent reconstruction of oral and maxillofacial defects with anterolateral thigh flaps and developed flap compromise from IJVT from July 2014 through December 2016 at the Second Xiangya Hospital of Central South University (Changsha, China). The clinical features of flap compromise are described, and the precautions and improvement measures are reported. RESULTS: All 13 patients were men with an average age of 50.3 years. Flap compromise caused by IJVT occurred on postoperative days 3 to 7, of which 2 flaps were salvaged (15.4%) and 11 flaps failed completely after immediate urgent re-exploration. Four patients presented with orocutaneous fistula after salvage surgery that healed well after a period of wound dressing. CONCLUSIONS: Because of the late occurrence and low salvage rate of flap compromise caused by IJVT, intensive flap monitoring after reconstruction surgery is necessary for patients with free flap transfer.

Novel compound heterozygous PANK2 gene mutations in a Chinese patient with atypical pantothenate kinase-associated neurodegeneration.

AIM: Pantothenate-kinase-associated neurodegeneration (PKAN), which is characterised by iron accumulation in the basal ganglia, is a rare autosomal recessive neurodegenerative disorder caused by pantothenate kinase 2 (PANK2) gene mutations. The PANK2 gene is located on chromosome 20p13 and encodes pantothenate kinase. Herein, we identified one patient with PKAN who had mutations in the PANK2 gene. MATERIALS AND METHODS: We performed clinical and radiographic investigations, and diagnosed this disease at the clinical and genetic levels. RESULTS: It is worth mentioning that the patient displayed an eye-of-the-tiger sign. Through scanning the exons and flanking intronic sequences of PANK2 in patient and control subjects, we report a compound heterozygote c. 260A > G (NM_001324191) and c.405dupC (NM_153638) for PANK2 mutations in a Chinese patient with clinical manifestation of progressive prosopospasm, dysarthria and gait disturbance. Bioinformatics analysis showed that two variants exhibited highly conserved residues across species. CONCLUSION: we reported a patient presenting with atypical PKAN, and identified novel compound heterozygous PANK2 gene mutations..

Reconstruction of Through-and-Through Oromandibular Defects With Combined Fibula Flap and Anterolateral Thigh Flap.

PURPOSE: The reconstruction of massive through-and-through oromandibular defects is still a challenge because no single adequate candidate for a donor site of vascularized bone and a large amount of soft tissue has yet been found. The aim of this study was to evaluate the feasibility and reconstructive efficacy of the combined fibula flap and anterolateral thigh (ALT) flap in tandem for the reconstruction of such defects. PATIENTS AND METHODS: We performed a retrospective case series of patients who had undergone reconstruction of through-and-through oromandibular defects with the combined fibula flap and ALT flap in tandem from January 2012 through December 2014 at the Second Xiangya Hospital. The flap design and the methods for defect reconstruction are described, and the reconstructive efficacy is reported. RESULTS: Of the 14 patients, 13 were men and 1 was a woman, with an average age of 49.36 years. Postoperatively, all flaps survived completely, without vascular compromise or major wound complications. All of the donor sites were closed directly, leaving only linear scars and no thigh or leg motor dysfunction. All patients were followed for approximately 12 to 48 months, and the appearance and oral functions were acceptably recovered in about 90% of the patients. CONCLUSIONS: Because of the convenient flap design, satisfactory functional and esthetic results, and lower complication rates at the donor and recipient sites, the use of a combined fibula flap and ALT flap in tandem is a good choice for the reconstruction of complex through-and-through oromandibular defects.

[Analyses of exercise-induced muscle damage-specific microRNA expression and molecular target of sarcolemmal damage in rats].

In the present study, we were to screen the specific microRNA (miRNA) of exercise-induced muscle damage (EIMD) and assess the EIMD-specific miRNAs-regulated target of sarcolemmal damage in rats. Twenty-four male Sprague-Dawley (SD) rats were randomly divided into 3 groups, which included sedentary (C), 24 h post-exercise (E24) and 48 h post-exercise (E48) groups. Rat EIMD model was established by an acute eccentric exercise, i.e., a downhill running treatment at -16º gradient. EIMD characteristics were verified by Evans blue dye staining, differentially expressed miRNAs were detected by microarray assay, EIMD-specific miRNAs expressions were further validated by real-time quantitative RT-PCR (RT-qPCR), and targets of the miRNAs were predicted based on mRNA expressions of associated proteins and related pathway core molecules of sarcolemmal damage. Two EIMD-specific expressed miRNAs, including miR-206-3p and miR-139-3p, were found in the study. There was a significantly negative correlation (P < 0.05) between miR-206-3p expression and dystrophin (r = -0.68), utrophin (r = -0.64), JNK (r = -0.62) or ERK1 (r = -0.68) respectively, but no correlation was found between miR-139-3p and these biomolecules. The results suggest that: i) the expression profile of miRNAs in rat is significantly affected by EIMD, ii) miR-206-3p and miR-139-3p are the EIMD-specific miRNAs, and iii) miR-206-3p may control sarcolemmal damage by regulating dystrophin, utrophin, JNK and ERK1.

Ataxia and hypogonadism caused by the loss of ubiquitin ligase activity of the U box protein CHIP.

Gordon Holmes syndrome (GHS) is a rare Mendelian neurodegenerative disorder characterized by ataxia and hypogonadism. Recently, it was suggested that disordered ubiquitination underlies GHS though the discovery of exome mutations in the E3 ligase RNF216 and deubiquitinase OTUD4. We performed exome sequencing in a family with two of three siblings afflicted with ataxia and hypogonadism and identified a homozygous mutation in STUB1 (NM_005861) c.737C→T, p.Thr246Met, a gene that encodes the protein CHIP (C-terminus of HSC70-interacting protein). CHIP plays a central role in regulating protein quality control, in part through its ability to function as an E3 ligase. Loss of CHIP function has long been associated with protein misfolding and aggregation in several genetic mouse models of neurodegenerative disorders; however, a role for CHIP in human neurological disease has yet to be identified. Introduction of the Thr246Met mutation into CHIP results in a loss of ubiquitin ligase activity measured directly using recombinant proteins as well as in cell culture models. Loss of CHIP function in mice resulted in behavioral and reproductive impairments that mimic human ataxia and hypogonadism. We conclude that GHS can be caused by a loss-of-function mutation in CHIP. Our findings further highlight the role of disordered ubiquitination and protein quality control in the pathogenesis of neurodegenerative disease and demonstrate the utility of combining whole-exome sequencing with molecular analyses and animal models to define causal disease polymorphisms.