Identification of Abundant and Functional dodecaRNAs (doRNAs) Derived from Ribosomal RNA.

Using a modified RNA-sequencing (RNA-seq) approach, we discovered a new family of unusually short RNAs mapping to ribosomal RNA 5.8S, which we named dodecaRNAs (doRNAs), according to the number of core nucleotides (12 nt) their members contain. Using a new quantitative detection method that we developed, we confirmed our RNA-seq data and determined that the minimal core doRNA sequence and its 13-nt variant C-doRNA (doRNA with a 5' Cytosine) are the two most abundant doRNAs, which, together, may outnumber microRNAs. The C-doRNA/doRNA ratio is stable within species but differed between species. doRNA and C-doRNA are mainly cytoplasmic and interact with heterogeneous nuclear ribonucleoproteins (hnRNP) A0, A1 and A2B1, but not Argonaute 2. Reporter gene activity assays suggest that C-doRNA may function as a regulator of Annexin II receptor (AXIIR) expression. doRNAs are differentially expressed in prostate cancer cells/tissues and may control cell migration. These findings suggest that unusually short RNAs may be more abundant and important than previously thought.

Nurturing and quiet intervention (NeuroN-QI) on preterm infants' neurodevelopment and maternal stress and anxiety: A pilot randomized clinical trial protocol.

OBJECTIVES: Primary objective of this pilot study is to evaluate the feasibility and acceptability of the NeuroN-QI and the study procedures. Secondary objectives are to assess the feasibility and acceptability of the NeuroN-QI by the nurses, assess the nurses' training needs about the components of the NeuroN-QI, and estimate the preliminary effects of the NeuroN-QI on infants' neurodevelopment as well as maternal stress and anxiety at infants' 36 weeks of gestational age. DESIGN: A two-group pilot parallel randomized clinical trial stratified by center. METHODS: The pilot study will be conducted in two neonatal intensive care units (NICUs). A sample of 24 mother-infant dyads born between 26 and 316/7 gestational age will be randomized into an experimental or control group. Fifty nurses will be recruited. The NeuroN-QI consists of four 2-hour skin-to-skin contact sessions/week with a 15-minute auditory stimulation by mothers with controlled ambient levels of light and noise. A 1-hour quiet period will follow where infants will rest in their incubator/crib with their mother's milk for olfactory stimulation and where the light and noise control will be continued. In the control group, mother-infant dyads will do four skin-to-skin contacts per week and receive standard care. Acceptability and feasibility of the NeuroN-QI in addition to maternal stress and anxiety will be measured through questionnaires, while infants' neurodevelopment will be assessed with Assessment of Preterm Infant Behaviour and General Movement Assessment. CONCLUSIONS: This pilot trial will address knowledge gaps and generate evidence in neonatal care by evaluating the feasibility and acceptability of a multi-component developmental care intervention. IMPACT: This project is an innovative step towards optimizing the neurodevelopmental trajectory of infants in NICUs and consequently promoting their long-term health outcomes. TRIAL REGISTRATION: NCT04593095.

Renal functional markers in extremely premature infants with and without twin-twin transfusion syndrome.

OBJECTIVE: Describe renal function of preterm infants <29 weeks of gestational age (GA) with twin-twin transfusion syndrome (TTTS) who received laser therapy. DESIGN: Retrospective analysis of premature TTTS compared with dichorionic-diamniotic (di-di) twins from 2006 to 2015. Primary outcome was biomarkers of renal injury. RESULTS: Thirty-three TTTS-laser and 101 di-di newborns with similar GA at birth (26.4 ± 1.4 vs 26.9 ± 1.6 weeks, p = 0.07) were included. Creatinine and urea levels were higher in TTTS-laser group at day of life (DOL) 2-7 (123.5 ± 12.4 vs 75.8 ± 2 µmol/L, p = 0.0001 and 11.9 ± 1.1 mmol/L vs 8.7 ± 0.3 mmol/L, p = 0.0001) and DOL 8-14, (98.1 ± 14.2 vs 64.8 ± 2.3 µmol/L, p = 0.0001 and 9.1 ± 1.2 vs 5.4 ± 0.3 mmol/L, p = 0.0001). There was a significant effect of TTTS status on creatinine level at DOL 8-14. CONCLUSION: In extremely preterm with TTTS treated by laser, biomarkers of renal function were higher compared with di-di twins in the first 2 weeks of life.

Outcomes of extremely premature infants with twin-twin transfusion syndrome treated by laser therapy.

OBJECTIVE: To compare short-term and long-term outcomes of preterm infants born at <29 weeks of gestational age (GA) with twin-twin transfusion syndrome (TTTS) treated with laser therapy to preterm twin infants without TTTS. DESIGN: Retrospective case-control study comparing 33 preterm TTTS twins to 101 preterm diamniotic-dichorionic (di-di) twins born at our institution between 2006 and 2015. RESULTS: GA at birth were 26.4 ± 1.4 weeks (TTTS) and 26.9 ± 1.6 weeks (di-di) (p = 0.07). TTTS premature newborns were less exposed to antenatal steroids (p = 0.01), more frequently born by C-section (p = 0.005), received more surfactant therapy (p = 0.004, and were smaller for GA (p < 0.001). When adjusted for antenatal steroids and birth weight, TTTS status was not associated with increased mortality (HR 1.66, 95% CI 0.77-3.56, p = 0.20). No differences were found on neurodevelopmental outcomes at 18 months of corrected GA. CONCLUSION: Premature TTTS newborns treated with fetal laser therapy had similar survival and neurodevelopmental outcomes compared to preterm di-di twins without TTTS.

Corticosteroid Therapy in Neonatal Septic Shock-Do We Prevent Death?

OBJECTIVE: The aim was to compare survival of patients with septic shock receiving or not hydrocortisone (HC) and to analyze the hemodynamic response to HC. STUDY DESIGN: It is a retrospective study of 62 premature neonates with septic shock (confirmed bacteremia) and/or necrotizing enterocolitis (NEC) stage 2 and above receiving inotropes with or without HC. We analyzed survival and hemodynamic response to HC. RESULTS: Thirty-nine (63%) premature neonates received HC and were compared with 23 (37%) who only received inotropes. Vasoactive index score (VAI) decreased and blood pressure, urine output, and oxygen requirements improved significantly following HC. Despite receiving more inotropes (VAI of 33 [20-53] vs 10 [8-20], p < 0.001), being more premature (26 ± 2 vs 27 ± 2 weeks, p = 0.02) and more frequently having NEC (64 vs 26%, p = 0.004), patients who received HC had similar survival from septic episode (death: 22% vs 41%, p = 0.12). However, patients receiving HC during their sepsis were less likely to survive at their 1-year postmenstrual age follow-up when accounted for gestational age (GA) at birth and duration of inotropes (hazard ratio 6.08 p = 0.01). CONCLUSION: HC was used in infants with increased inotropic support. HC during septic shock was associated with similar survival from episode, but with decreased survival at 1-year postmenstrual age.

Breast Cancer Risk Estimation and Personal Insurance: A Qualitative Study Presenting Perspectives from Canadian Patients and Decision Makers.

Genetic stratification approaches in personalized medicine may considerably improve our ability to predict breast cancer risk for women at higher risk of developing breast cancer. Notwithstanding these advantages, concerns have been raised about the use of the genetic information derived in these processes, outside of the research and medical health care settings, by third parties such as insurers. Indeed, insurance applicants are asked to consent to insurers accessing their medical information (implicitly including genetic) to verify or determine their insurability level, or eligibility to certain insurance products. This use of genetic information may result in the differential treatment of individuals based on their genetic information, which could lead to higher premium, exclusionary clauses or even the denial of coverage. This phenomenon has been commonly referred to as "Genetic Discrimination" (GD). In the Canadian context, where federal Bill S-201, An Act to prohibit and prevent genetic discrimination, has recently been enacted but may be subject to constitutional challenges, information about potential risks to insurability may raise issues in the clinical context. We conducted a survey with women in Quebec who have never been diagnosed with breast cancer to document their perspectives. We complemented the research with data from 14 semi-structured interviews with decision-makers in Quebec to discuss institutional issues raised by the use of genetic information by insurers. Our results provide findings on five main issues: (1) the reluctance to undergo genetic screening test due to insurability concerns, (2) insurers' interest in genetic information, (3) the duty to disclose genetic information to insurers, (4) the disclosure of potential impacts on insurability before genetic testing, and (5) the status of genetic information compared to other health data. Overall, both groups of participants (the women surveyed and the decision-makers interviewed) acknowledged having concerns about GD and reported a need for better communication tools discussing insurability risk. Our conclusions regarding concerns about GD and the need for better communication tools in the clinical setting may be transferable to the broader Canadian context.

microRNA-132/212 deficiency enhances Aß production and senile plaque deposition in Alzheimer's disease triple transgenic mice.

The abnormal regulation of amyloid-ß (Aß) metabolism (e.g., production, cleavage, clearance) plays a central role in Alzheimer's disease (AD). Among endogenous factors believed to participate in AD progression are the small regulatory non-coding microRNAs (miRs). In particular, the miR-132/212 cluster is severely reduced in the AD brain. In previous studies we have shown that miR-132/212 deficiency in mice leads to impaired memory and enhanced Tau pathology as seen in AD patients. Here we demonstrate that the genetic deletion of miR-132/212 promotes Aß production and amyloid (senile) plaque formation in triple transgenic AD (3xTg-AD) mice. Using RNA-Seq and bioinformatics, we identified genes of the miR-132/212 network with documented roles in the regulation of Aß metabolism, including Tau, Mapk, and Sirt1. Consistent with these findings, we show that the modulation of miR-132, or its target Sirt1, can directly regulate Aß production in cells. Finally, both miR-132 and Sirt1 levels correlated with Aß load in humans. Overall, our results support the hypothesis that the miR-132/212 network, including Sirt1 and likely other target genes, contributes to abnormal Aß metabolism and senile plaque deposition in AD. This study strengthens the importance of miR-dependent networks in neurodegenerative disorders, and opens the door to multifactorial drug targets of AD by targeting Aß and Tau.

In extremely preterm infants, do the Movement Assessment of Infants and the Alberta Infant Motor Scale predict 18-month outcomes using the Bayley-III?

BACKGROUND: Extremely preterm infants are at high-risk for neurodevelopmental disabilities. The Movement Assessment of Infants (MAI) and the Alberta Infant Motor Scale (AIMS) have been designed to predict outcome with modest accuracy with the Bayley-I or Bayley-II. AIMS: To examine and compare the predictive validity of the MAI and AIMS in determining neurodevelopmental outcome with the Bayley-III. DESIGN: Retrospective cohort study of 160 infants born at ≤ 28 weeks gestation. METHOD: At their corrected age, infants underwent the MAI at 4 months, the AIMS at 4 and 10-12 months, and the Bayley-III and neurological examination at 18 months. Sensitivity and specificity were calculated. RESULTS: Infants had a mean gestation of 26.3 ± 1.4 weeks and birth weight of 906 ± 207 g. A high-risk score (≥ 14) for adverse outcome was obtained by 57% of infants on the MAI. On the AIMS, a high-risk score (<5th percentile) was obtained by 56% at 4 months and 30% at 10-12 months. At 18 months, infants with low-risk scores on either the MAI or AIMS had higher cognitive, language, and motor Bayley-III scores than those with high-risk scores. They were less likely to have severe neurodevelopmental impairment. To predict Bayley-III scores <70, sensitivity and specificity were 91% and 49%, respectively, for the MAI and 78% and 48%, respectively, for the AIMS. CONCLUSIONS: Extremely preterm infants with low-risk MAI at 4 months or AIMS scores at 4 or 10-12 months had better outcomes than those with high-risk scores. However, both tests lack specificity to predict individual neurodevelopmental status at 18 months.

Mutation in the 3'untranslated region of APP as a genetic determinant of cerebral amyloid angiopathy.

Aß-related cerebral amyloid angiopathy (CAA) is a major cause of primary non-traumatic brain hemorrhage. In families with an early onset of the disease, CAA can be due to amyloid precursor protein (APP) pathogenic variants or duplications. APP duplications lead to a ~1.5-fold increased APP expression, resulting in Aß overproduction and deposition in the walls of leptomeningeal vessels. We hypothesized that rare variants in the 3'untranslated region (UTR) of APP might lead to APP overexpression in patients with CAA and no APP pathogenic variant or duplication. We performed direct sequencing of the whole APP 3'UTR in 90 patients with CAA and explored the functional consequences of one previously unreported variant. We identified three sequence variants in four patients, of which a two-base pair deletion (c.*331_*332del) was previously unannotated and absent from 175 controls of same ethnicity. This latter variant was associated with increased APP expression in vivo and in vitro. Bioinformatics and functional assays showed that the APP c.*331_*332del variant affected APP messenger RNA (mRNA) structure and binding of two microRNAs (miR-582-3p and miR-892b), providing a mechanism for the observed effects on APP expression. These results identify APP 3'UTR sequence variants as genetic determinants of Aß-CAA.

Preclinical Evaluation of miR-15/107 Family Members as Multifactorial Drug Targets for Alzheimer's Disease.

Alzheimer's disease (AD) is a multifactorial, fatal neurodegenerative disorder characterized by the abnormal accumulation of Aß and Tau deposits in the brain. There is no cure for AD, and failure at different clinical trials emphasizes the need for new treatments. In recent years, significant progress has been made toward the development of miRNA-based therapeutics for human disorders. This study was designed to evaluate the efficiency and potential safety of miRNA replacement therapy in AD, using miR-15/107 paralogues as candidate drug targets. We identified miR-16 as a potent inhibitor of amyloid precursor protein (APP) and BACE1 expression, Aß peptide production, and Tau phosphorylation in cells. Brain delivery of miR-16 mimics in mice resulted in a reduction of AD-related genes APP, BACE1, and Tau in a region-dependent manner. We further identified Nicastrin, a γ-secretase component involved in Aß generation, as a target of miR-16. Proteomics analysis identified a number of additional putative miR-16 targets in vivo, including α-Synuclein and Transferrin receptor 1. Top-ranking biological networks associated with miR-16 delivery included AD and oxidative stress. Collectively, our data suggest that miR-16 is a good candidate for future drug development by targeting simultaneously endogenous regulators of AD biomarkers (i.e., Aß and Tau), inflammation, and oxidative stress.

miR-132/212 deficiency impairs tau metabolism and promotes pathological aggregation in vivo.

Alzheimer's disease (AD) and related tauopathies comprise a large group of neurodegenerative diseases associated with the pathological aggregation of tau protein. While much effort has focused on understanding the function of tau, little is known about the endogenous mechanisms regulating tau metabolism in vivo and how these contribute to disease. Previously, we have shown that the microRNA (miRNA) cluster miR-132/212 is downregulated in tauopathies such as AD. Here, we report that miR-132/212 deficiency in mice leads to increased tau expression, phosphorylation and aggregation. Using reporter assays and cell-based studies, we demonstrate that miR-132 directly targets tau mRNA to regulate its expression. We identified GSK-3ß and PP2B as effectors of abnormal tau phosphorylation in vivo. Deletion of miR-132/212 induced tau aggregation in mice expressing endogenous or human mutant tau, an effect associated with autophagy dysfunction. Conversely, treatment of AD mice with miR-132 mimics restored in part memory function and tau metabolism. Finally, miR-132 and miR-212 levels correlated with insoluble tau and cognitive impairment in humans. These findings support a role for miR-132/212 in the regulation of tau pathology in mice and humans and provide new alternatives for therapeutic development.

MicroRNAs targeting Nicastrin regulate Aß production and are affected by target site polymorphisms.

Despite the growing number of genome-wide association studies, the involvement of polymorphisms in microRNA target sites (polymiRTS) in Alzheimer's disease (AD) remains poorly investigated. Recently, we have shown that AD-associated single-nucleotide polymorphisms (SNPs) present in the 3' untranslated region (3'UTR) of amyloid precursor protein (APP) could directly affect miRNA function. In theory, loss of microRNA (miRNA) function could lead to risk for AD by increasing APP expression and Aß peptide production. In this study, we tested the hypothesis that Nicastrin, a γ-secretase subunit involved in Aß generation, could be regulated by miRNAs, and consequently affected by 3'UTR polymorphisms. Bioinformatic analysis identified 22 putative miRNA binding sites located in or near Nicastrin 3'UTR polymorphisms. From these miRNA candidates, six were previously shown to be expressed in human brain. We identified miR-24, miR-186, and miR-455 as regulators of Nicastrin expression, both in vitro and under physiological conditions in human cells, which resulted in altered Aß secretion. Using luciferase-based assays, we further demonstrated that rs113810300 and rs141849450 SNPs affected miRNA-mediated repression of Nicastrin. Notably, rs141849450 completely abolished the miR-455-mediated repression of Nicastrin. Finally, the rs141849450 variant was identified in 1 out of 511 AD cases but not in 631 controls. These observations set the stage for future studies exploring the role of miRNAs and 3'UTR polymorphisms in AD.

Gene and MicroRNA transcriptome analysis of Parkinson's related LRRK2 mouse models.

Mutations in leucine-rich repeat kinase 2 (LRRK2) are the most frequent cause of genetic Parkinson's disease (PD). The biological function of LRRK2 and how mutations lead to disease remain poorly defined. It has been proposed that LRRK2 could function in gene transcription regulation; however, this issue remains controversial. Here, we investigated in parallel gene and microRNA (miRNA) transcriptome profiles of three different LRRK2 mouse models. Striatal tissue was isolated from adult LRRK2 knockout (KO) mice, as well as mice expressing human LRRK2 wildtype (hLRRK2-WT) or the PD-associated R1441G mutation (hLRRK2-R1441G). We identified a total of 761 genes and 24 miRNAs that were misregulated in the absence of LRRK2 when a false discovery rate of 0.2 was applied. Notably, most changes in gene expression were modest (i.e., <2 fold). By real-time quantitative RT-PCR, we confirmed the variations of selected genes (e.g., adra2, syt2, opalin) and miRNAs (e.g., miR-16, miR-25). Surprisingly, little or no changes in gene expression were observed in mice expressing hLRRK2-WT or hLRRK2-R1441G when compared to non-transgenic controls. Nevertheless, a number of miRNAs were misexpressed in these models. Bioinformatics analysis identified several miRNA-dependent and independent networks dysregulated in LRRK2-deficient mice, including PD-related pathways. These results suggest that brain LRRK2 plays an overall modest role in gene transcription regulation in mammals; however, these effects seem context and RNA type-dependent. Our data thus set the stage for future investigations regarding LRRK2 function in PD development.

Circulating microRNAs in Alzheimer's disease: the search for novel biomarkers.

Alzheimer's disease (AD) is the most common neurodegenerative disease in the elderly. While advancements have been made in understanding the genetic and molecular basis of AD, the clinical diagnosis of AD remains difficult, and post-mortem confirmation is often required. Furthermore, the onset of neurodegeneration precedes clinical symptoms by approximately a decade. Consequently, there is a crucial need for an early and accurate diagnosis of AD, which can potentially lead to strategies that can slow down or stop the progression of neurodegeneration and dementia. Recent advances in the non-coding RNA field have shown that microRNAs (miRNAs) can function as powerful biomarkers in human diseases. Studies are emerging suggesting that circulating miRNAs in the cerebrospinal fluid and blood serum have characteristic changes in AD patients. Whether miRNAs can be used in AD diagnosis, alone or in combination with other AD biomarkers (e.g., amyloid and tau), warrants further investigation.

Gene network and pathway analysis of mice with conditional ablation of Dicer in post-mitotic neurons.

BACKGROUND: The small non-protein-coding microRNAs (miRNAs) have emerged as critical regulators of neuronal differentiation, identity and survival. To date, however, little is known about the genes and molecular networks regulated by neuronal miRNAs in vivo, particularly in the adult mammalian brain. METHODOLOGY/PRINCIPAL FINDINGS: We analyzed whole genome microarrays from mice lacking Dicer, the enzyme responsible for miRNA production, specifically in postnatal forebrain neurons. A total of 755 mRNA transcripts were significantly (P<0.05, FDR<0.25) misregulated in the conditional Dicer knockout mice. Ten genes, including Tnrc6c, Dnmt3a, and Limk1, were validated by real time quantitative RT-PCR. Upregulated transcripts were enriched in nonneuronal genes, which is consistent with previous studies in vitro. Microarray data mining showed that upregulated genes were enriched in biological processes related to gene expression regulation, while downregulated genes were associated with neuronal functions. Molecular pathways associated with neurological disorders, cellular organization and cellular maintenance were altered in the Dicer mutant mice. Numerous miRNA target sites were enriched in the 3'untranslated region (3'UTR) of upregulated genes, the most significant corresponding to the miR-124 seed sequence. Interestingly, our results suggest that, in addition to miR-124, a large fraction of the neuronal miRNome participates, by order of abundance, in coordinated gene expression regulation and neuronal maintenance. CONCLUSIONS/SIGNIFICANCE: Taken together, these results provide new clues into the role of specific miRNA pathways in the regulation of brain identity and maintenance in adult mice.

LRRK2 in Transcription and Translation Regulation: Relevance for Parkinson's Disease.

Parkinson's disease (PD) is the most common neurodegenerative movement disorder and is characterized by the selective loss of dopaminergic neurons and the presence of Lewy bodies. Mutations in the leucine-rich repeat kinase 2 (LRRK2) gene are the most frequent cause of both familial and sporadic PD. One critical question is how PD-associated LRRK2 mutations cause neurodegeneration. Here, we discuss recent findings related to LRRK2-mediated regulation of gene expression and translation and provide a critical assessment of the current models that are used to address the impact of LRRK2 on the transcriptome. A better understanding of these mechanisms could provide important new clues into the function of LRRK2 during both normal and pathological conditions.

Hypoglycemia in term newborns with a birth weight below the 10th percentile.

BACKGROUND: Current recommendations suggest that routine screening for hypoglycemia should be performed in all term newborns with a birth weight (BW) below the 10th percentile. The impact of updated growth curves on the incidence of hypoglycemia in small-for-gestational-age (SGA) newborns has not been evaluated. OBJECTIVES: To evaluate the occurrence and severity of hypoglycemia in term newborns with a BW between the 10th and fifth percentile, and below the fifth percentile, using recently updated growth curves. DESIGN: A one-year prospective cohort study. METHODS: Inclusion criteria were gestational age of 37 weeks or greater and BW below the 10th percentile. Neonatal hypoglycemia was defined as a blood glucose level of less than 2.6 mmol/L measured after 2 h of life. Blood glucose was measured routinely for all SGA infants during the first 36 h of life. RESULTS: A total of 187 SGA infants met the study criteria: 85 infants with a BW between the 10th and fifth percentile, and 102 infants with a BW below the fifth percentile. The characteristics of the study cohort were similar between BW groups. Twenty-six per cent of the infants screened had at least one episode of hypoglycemia: 22% of infants in the 10th to fifth percentile group and 28% in the less than fifth percentile group. Hypoglycemia was symptomatic in four infants, all of whom were below the fifth percentile for BW. The mean (± SD) lowest blood glucose level was 2.1±0.4 mmol/L (range 0.6 mmol/L to 2.5 mmol/L) in the 10th to fifth percentile group and 2.0±0.5 mmol/L (range 0.8 mmol/L to 2.5 mmol/L) in the less than fifth percentile group (P=0.05). CONCLUSION: The present study demonstrates a high incidence of hypoglycemia among SGA infants with a BW below the 10th percentile using updated growth curves. There was no difference in the incidence of hypoglycemia among SGA infants with a BW below the fifth percentile versus those with a BW between the 10th and fifth percentile.

Screening HIV in pregnancy: a survey of prenatal care patients.

BACKGROUND: Women in Canada, as in the rest of the world, represent an increasing proportion of new HIV positive cases. In 2002, women accounted for 25% of all positive HIV tests reported in Canada; with the majority being in their childbearing years (15 to 39 years), perinatal transmission of HIV in Canada is cause for concern. Following the development of interventions that can effectively reduce vertical transmission rate, prenatal screening of HIV has become the first and most pivotal step in the prevention of mother-to-child HIV transmission. The purpose of this study was to assess how women's knowledge and attitudes regarding HIV and HIV screening in pregnancy influence screening rates. METHOD: A prospective anonymous survey of 231 women attending antenatal care clinics at a teaching university hospital or in a community clinic was conducted. RESULTS: In general, pregnant women supported universal HIV screening in the prenatal period. Women who previously had been tested for HIV and who did not perceive that they were at risk for contracting HIV were more likely to decline HIV testing in their current pregnancy. Overall knowledge regarding HIV and its transmission is less than optimal, particularly among those women who declined HIV testing. CONCLUSION: Knowledge gaps exist between women accepting and declining prenatal HIV screening, particularly relating to benefits of screening. These results suggest that efforts have to continue to be put into educating the public but also, importantly, into changing current attitudes.

SUMO on the road to neurodegeneration.

Sumoylation is a post-translational modification by which small ubiquitin-like modifiers (SUMO) are covalently conjugated to target proteins. This reversible pathway provides a rapid and efficient way to modulate the subcellular localization, activity and stability of a wide variety of substrates. Similar to its well-known cousin ubiquitin, SUMO co-localize with the neuronal inclusions associated with several neurodegenerative diseases, including multiple system atrophy, Huntington's disease and other related polyglutamine disorders. The identification of huntingtin, ataxin-1, tau and alpha-synuclein as SUMO substrates further supports the involvement of sumoylation in the pathogenesis of this family of neurological diseases. In addition to direct targeting of these constituent proteins, sumoylation also impacts other disease pathways such as oxidative stress, protein aggregation and proteasome-mediated degradation. This review highlights the recent advances in understanding the contributions of SUMO to neurodegeneration and the underlying pathogenic mechanisms of these diseases.