Renal protection after hemorrhagic shock in rats: Possible involvement of SUMOylation.

Hemorrhagic shock (HS), a leading cause of preventable death, is characterized by severe blood loss and inadequate tissue perfusion. Reoxygenation of ischemic tissues exacerbates organ damage through ischemia-reperfusion injury. SUMOylation has been shown to protect neurons after stroke and is upregulated in response to cellular stress. However, the role of SUMOylation in organ protection after HS is unknown. This study aimed to investigate SUMOylation-mediated organ protection following HS. Male Wistar rats were subjected to HS (blood pressure of 40 ± 2 mmHg, for 90 min) followed by reperfusion. Blood, kidney, and liver samples were collected at various time points after reperfusion to assess organ damage and investigate the profile of SUMO1 and SUMO2/3 conjugation. In addition, human kidney cells (HK-2), treated with the SUMOylation inhibitor TAK-981 or overexpressing SUMO proteins, were subjected to oxygen and glucose deprivation to investigate the role of SUMOylation in hypoxia/reoxygenation injury. The animals presented progressive multiorgan dysfunction, except for the renal system, which showed improvement over time. Compared to the liver, the kidneys displayed distinct patterns in terms of oxidative stress, apoptosis activation, and tissue damage. The global level of SUMO2/3 in renal tissue was also distinct, suggesting a differential role. Pharmacological inhibition of SUMOylation reduced cell viability after hypoxia-reoxygenation damage, while overexpression of SUMO1 or SUMO2 protected the cells. These findings suggest that SUMOylation might play a critical role in cellular protection during ischemia-reperfusion injury in the kidneys, a role not observed in the liver. This difference potentially explains the renal resilience observed in HS animals when compared to other systems.

Worldwide prevalence of sleep problems in community-dwelling older adults: A systematic review and meta-analysis.

The understanding of the prevalence of sleep problems in older adults can provide a broad and reliable perspective into the occurrence of such issues among older adults. This systematic review and meta-analysis aimed to estimate the worldwide prevalence of sleep problems in community-dwelling older adults. Studies that provide information on the prevalence of sleep problems in community-dwelling older adults (≥60 years) were screened between December 2022 and March 2023. A total of 20,379 studies were identified in database searches, from which 252 were included in this review. These studies covered the last 35 years (from 1988 to 2023) and pooled a sample of 995,544 participants from 36 countries. The most frequent sleep problem worldwide was obstructive sleep apnea (46.0%), followed by poor sleep quality (40.0%), other sleep problems (37.0%), insomnia (29.0%), and excessive daytime sleepiness (19.0%). No significant difference in the prevalence estimates of all sleep problems was observed between the sexes. This systematic review and meta-analysis showed a high prevalence of some sleep problems, mainly obstructive sleep apnea, poor sleep quality, and other sleep problems. Our estimates can be useful for managers and policymakers in planning healthcare strategies for sleep problems aimed at the older population.

SUMOylation effects on neural stem cells self-renewal, differentiation, and survival.

SUMO (small ubiquitin-like modifier) conjugation or SUMOylation, a post-translational modification, is a crucial regulator of protein function and cellular processes. In the context of neural stem cells (NSCs), SUMOylation has emerged as a key player, affecting their proliferation, differentiation, and survival. By modifying transcription factors, such as SOX1, SOX2, SOX3, SOX6, Bmi1, and Nanog, SUMOylation can either enhance or impair their transcriptional activity, thus impacting on NSCs self-renewal. Moreover, SUMOylation regulates neurogenesis and neuronal differentiation by modulating key proteins, such as Foxp1, Mecp2, MEF2A, and SOX10. SUMOylation is also crucial for the survival and proliferation of NSCs in both developing and adult brains. By regulating the activity of transcription factors, coactivators, and corepressors, SUMOylation acts as a molecular switch, inducing cofactor recruitment and function during development. Importantly, dysregulation of NSCs SUMOylation has been implicated in various disorders, including embryonic defects, ischemic cerebrovascular disease, glioma, and the harmful effects of benzophenone-3 exposure. Here we review the main findings on SUMOylation-mediated regulation of NSCs self-renewal, differentiation and survival. Better understanding NSCs SUMOylation mechanisms and its functional consequences might provide new strategies to promote neuronal differentiation that could contribute for the development of novel therapies targeting neurodegenerative diseases.

A nationwide study on sleep complaints and associated factors in older adults: ELSI-Brazil.

Sleep problems, such as difficulty falling asleep, staying asleep, early awakening with failure to continue sleep, and altered sleep-wake cycle, are common in the general population. This cross-sectional study with 6,929 older adults (≥ 60 years) aimed to estimate the prevalence of different types of sleep problems, their associated factors, and the population-attributable fraction of associated factors among older adults. The outcome variables consisted of self-reported sleep problems: insomnia (initial, intermediate, late, and any type of insomnia), poor sleep quality, and daytime sleepiness. The independent variables were sociodemographic and behavioral characteristics and health conditions. The prevalence proportions were initial insomnia (49.1%), intermediate insomnia (49.2%), late insomnia (45.9%), any type of insomnia (58.6%), poor sleep quality (15.6%), and daytime sleepiness (38.4%). Female sex, presence of two or more chronic diseases, not eating the recommended amount of fruits and vegetables, and regular and bad/very bad self-rated health were positively associated with the sleep problems investigated. Consuming alcohol once a month or more was inversely associated with initial insomnia. Population attributable fraction estimates ranged from 3% to 19% considering two or more chronic diseases, not eating the recommended amount of fruits and vegetables, and regular and bad/very bad self-rated health. High prevalence of self-reported sleep problems was evinced in older adults. These results can be useful to guide public health services in the creation of informational, evaluative, and screening strategies for sleep problems in older Brazilian adults.

Guanosine increases global SUMO1-ylation in the hippocampus of young and aged mice and improves the short-term memory of young mice.

The nucleoside guanosine is an endogenous neuromodulator associated with neuroprotection. The roles of guanosine during aging are still not fully elucidated. Guanosine modulates SUMOylation in neurons and astrocytes in vitro, but it is not known whether guanosine can modulate SUMOylation in vivo and improve cognitive functions during aging. SUMOylation is a post-translational protein modification with potential neuroprotective roles. In this follow-up study, we investigated whether guanosine could modulate SUMOylation in vivo and behavior in young and aged mice. Young (3-month-old) and aged (24-month-old) C57BL/6 mice were treated with guanosine (8 mg/kg intraperitoneal) daily for 14 days. Starting on day 8 of treatment, the following behavioral tests were performed: open field, novel object location, Y-maze, sucrose splash test, and tail suspension test. Treatment with guanosine did not change the locomotor activity of young or aged mice in the open-field test. Treatment with guanosine improved short-term memory only for young mice but did not change the working memory of either young or aged mice, as evaluated using object recognition and the Y-maze tests, respectively. Depressive-like behaviors, such as impaired grooming evaluated through the splash test, did not change in either young or aged mice. However, young mice treated with guanosine increased their immobility time in the tail suspension test, suggesting an effect on behavioral coping strategies. Global SUMO1-ylation was significantly increased in the hippocampus of young and aged mice after 14 days of treatment with guanosine, whereas no changes were detected in the cerebral cortex of either young or aged mice. Our findings demonstrate that guanosine also targets hippocampal SUMOylation in vivo, thereby contributing to a deeper understanding of its mechanisms of action. This highlights the involvement of SUMOylation in guanosine's modulatory and neuroprotective effects.

Circadian rhythm alterations affecting the pathology of neurodegenerative diseases.

The circadian rhythm is a nearly 24-h oscillation found in various physiological processes in the human brain and body that is regulated by environmental and genetic factors. It is responsible for maintaining body homeostasis and it is critical for essential functions, such as metabolic regulation and memory consolidation. Dysregulation in the circadian rhythm can negatively impact human health, resulting in cardiovascular and metabolic diseases, psychiatric disorders, and premature death. Emerging evidence points to a relationship between the dysregulation circadian rhythm and neurodegenerative diseases, suggesting that the alterations in circadian function might play crucial roles in the pathogenesis and progression of neurodegenerative diseases. Better understanding this association is of paramount importance to expand the knowledge on the pathophysiology of neurodegenerative diseases, as well as, to provide potential targets for the development of new interventions based on the dysregulation of circadian rhythm. Here we review the latest findings on dysregulation of circadian rhythm alterations in Parkinson's disease, Alzheimer's disease, Huntington's disease, amyotrophic lateral sclerosis, multiple sclerosis, spinocerebellar ataxia and multiple-system atrophy, focusing on research published in the last 3 years.

A nationwide study on pain manifestations and sleep problems in community-dwelling older adults: findings from ELSI-Brazil.

PURPOSE: Sleep problems are common and affect approximately 36-70% of older adults worldwide and can be associated with negative outcomes such as pain. There is believed to be a bidirectional relationship between sleep problems and pain, modulated by inflammation and stress. The objective was to investigate the association between self-reported sleep problems and pain manifestations. METHODS: A cross-sectional study using data from the second wave of the Brazilian Longitudinal Study of Aging (2019-2021) was conducted. The exposure variables were self-reported sleep problems: poor sleep quality, insomnia (initial, intermediate, and final), and daytime sleepiness. The outcomes were self-reported pain manifestations: frequent pain, moderate/intense/strong pain, and pain-related disability. Logistic regressions were performed to verify the association between exposures and outcomes. RESULTS: A total of 6875 community-dwelling older adults participated in this study (71.1 ± 8.3 years; 54.4% female). Older adults with self-reported poor sleep quality, initial, intermediate and final insomnia, and daytime sleepiness had, respectively, 1.99 (95% CI 1.57-2.53), 1.47 (95% CI 1.11-1.97), 1.65 (95% CI 1.27-2.14), 1.69 (95% CI 1.29-2.22), and 1.76 (95% CI 1.35-2.29) greater odds of reporting frequent pain. The odds of moderate/intense/strong pain were higher in older adults that reported poor sleep quality (OR: 2.21; 95% CI 1.08-4.51). Older adults with self-reported poor sleep quality, initial, intermediate and final insomnia, and daytime sleepiness had, respectively, 1.84 (95% CI 1.11-3.02), 1.73 (95% CI 1.14-2.62), 1.80 (95% CI 1.19-2.73), 1.58 (95% CI 1.07-2.34), and 1.63 (95% CI 1.11-2.39) greater odds of reporting pain-related disability. CONCLUSION: Self-reported sleep problems are associated with pain manifestations in older adults. The results may help in the proposition of programs and public health policies.

Targeting α-synuclein post-translational modifications in Parkinson's disease.

Parkinson's disease (PD) is a neurodegenerative disease characterized by the progressive loss of dopaminergic neurons in the nigrostriatal pathway. Although the exact mechanisms underlying PD are still not completely understood, it is well accepted that α-synuclein plays key pathophysiological roles as the main constituent of the cytoplasmic inclusions known as Lewy bodies. Several post-translational modifications (PTMs), such as the best-known phosphorylation, target α-synuclein and are thus implicated in its physiological and pathological functions. In this review, we present (1) an overview of the pathophysiological roles of α-synuclein, (2) a descriptive analysis of α-synuclein PTMs, including phosphorylation, ubiquitination, SUMOylation, acetylation, glycation, truncation, and O-GlcNAcylation, as well as (3) a brief summary on α-synuclein PTMs as potential biomarkers for PD. A better understanding of α-synuclein PTMs is of paramount importance for elucidating the mechanisms underlying PD and can thus be expected to improve early detection and monitoring disease progression, as well as identify promising new therapeutic targets.

A nationwide study on sleep complaints and associated factors in older adults: ELSI-Brazil / Estudo nacional sobre queixas de sono e fatores associados em idosos: ELSI-Brasil / Estudio nacional sobre quejas de sueño y factores asociados en adultos mayores: ELSI-Brasil

Abstract: Sleep problems, such as difficulty falling asleep, staying asleep, early awakening with failure to continue sleep, and altered sleep-wake cycle, are common in the general population. This cross-sectional study with 6,929 older adults (≥ 60 years) aimed to estimate the prevalence of different types of sleep problems, their associated factors, and the population-attributable fraction of associated factors among older adults. The outcome variables consisted of self-reported sleep problems: insomnia (initial, intermediate, late, and any type of insomnia), poor sleep quality, and daytime sleepiness. The independent variables were sociodemographic and behavioral characteristics and health conditions. The prevalence proportions were initial insomnia (49.1%), intermediate insomnia (49.2%), late insomnia (45.9%), any type of insomnia (58.6%), poor sleep quality (15.6%), and daytime sleepiness (38.4%). Female sex, presence of two or more chronic diseases, not eating the recommended amount of fruits and vegetables, and regular and bad/very bad self-rated health were positively associated with the sleep problems investigated. Consuming alcohol once a month or more was inversely associated with initial insomnia. Population attributable fraction estimates ranged from 3% to 19% considering two or more chronic diseases, not eating the recommended amount of fruits and vegetables, and regular and bad/very bad self-rated health. High prevalence of self-reported sleep problems was evinced in older adults. These results can be useful to guide public health services in the creation of informational, evaluative, and screening strategies for sleep problems in older Brazilian adults.

Resumo: Problemas de sono, como dificuldade para adormecer, permanecer dormindo, despertar precoce com falha na continuidade do sono e alteração do ciclo vigília-sono, são comuns na população em geral. Este estudo transversal com 6.929 idosos (≥ 60 anos) buscou estimar a prevalência de diferentes tipos de problemas de sono, seus fatores associados e a fração atribuível populacional de fatores associados a problemas de sono nessa população. As variáveis de desfecho foram problemas de sono autorreferidos: insônia (inicial, intermediária, tardia e qualquer tipo de insônia), má qualidade do sono e sonolência diurna. As variáveis independentes incluíram características sociodemográficas, comportamentais e condições de saúde. As proporções de prevalência foram: insônia inicial (49,1%), insônia intermediária (49,2%), insônia tardia (45,9%), qualquer tipo de insônia (58,6%), má qualidade do sono (15,6%) e sonolência diurna (38,4%). Sexo feminino, presença de duas ou mais doenças crônicas, não consumir a quantidade recomendada de frutas e hortaliças e autoavaliação da saúde como regular e ruim/muito ruim mostraram associação positiva aos problemas de sono investigados. Consumo de álcool uma vez por mês ou mais associou-se inversamente à insônia inicial. As estimativas da fração atribuível populacional variaram de 3% a 19% considerando duas ou mais doenças crônicas, consumo insuficiente de frutas e vegetais e saúde autorrelatada regular/ruim/muito ruim. Evidenciou-se alta prevalência de problemas de sono autorreferidos em idosos. Esses resultados podem orientar os serviços públicos de saúde na criação de estratégias informativas, avaliativas e de rastreamento de problemas de sono em idosos brasileiros.

Resumen: Problemas del sueño, como la dificultad para conciliar el sueño, permanecer dormido, despertarse temprano sin poder seguir durmiendo y cambios en el ciclo de sueño y vigilia, son comunes en la población en general. Este estudio transversal con 6.929 personas mayores (≥ 60 años) buscó estimar la prevalencia de diferentes tipos de problemas de sueño, sus factores asociados y la fracción atribuible a la población de factores asociados con problemas de sueño en esta población. Las variables de desenlace fueron problemas de sueño autoinformados: insomnio (inicial, intermedio, tardío y cualquier tipo de insomnio), mala calidad del sueño y somnolencia diurna. Las variables independientes incluyeron características sociodemográficos y conductuales y condiciones de salud. Estas fueron las proporciones de prevalencia: insomnio inicial (49,1%), insomnio intermedio (49,2%), insomnio tardío (45,9%), cualquier tipo de insomnio (58,6%), mala calidad del sueño (15,6%) y somnolencia diurna (38,4%). El sexo femenino, la presencia de dos o más enfermedades crónicas, no consumir la cantidad recomendada de frutas y hortalizas y la autoevaluación de la salud como regular y mala/muy mala mostraron una asociación positiva con los problemas de sueño investigados. El consumo de alcohol una vez al mes o más se asoció inversamente con el insomnio inicial. Las estimaciones de la fracción atribuible de la población oscilaron entre el 3% y el 19% considerando dos o más enfermedades crónicas, un consumo insuficiente de frutas y verduras y una salud autoinformada regular/mala/muy mala. Se evidenció una alta prevalencia de problemas de sueño autoinformados en las personas mayores. Estos resultados pueden orientar los servicios públicos de salud en la creación de estrategias informativas, evaluativas y de seguimiento de los problemas de sueño en las personas mayores brasileñas.

Neuroprotective potential of the Amazonian fruits Euterpe oleracea Mart. and Paullinia cupana Kunth

Abstract Acai (Euterpe oleracea Mart.) and guarana (Paullinia cupana Kunth) are native species from the Amazon Forest that in folk medicine are used to treat several diseases due to their anti-inflammatory and antioxidant properties. This review brings together findings from different studies on the potential neuroprotective effects of acai and guarana, highlighting the importance of the conservation and sustainable exploitation of the Amazon Forest. A bibliographic survey in the PubMed database retrieved indexed articles written in English that focused on the effects of acai and guarana in in vitro and in vivo models of neurodegenerative diseases. In general, treatment with either acai or guarana decreased neuroinflammation, increased antioxidant responses, ameliorated depression, and protected cells from neurotoxicity mediated by aggregated proteins. The results from these studies suggest that flavonoids, anthocyanins, and carotenoids found in both acai and guarana have therapeutic potential not only for neurodegenerative diseases, but also for depressive disorders. In addition, acai and guarana show beneficial effects in slowing down the physiological aging process. However, toxicity and efficacy studies are still needed to guide the formulation of herbal medicines from acai and guarana.

SUMOylation in peripheral tissues under low perfusion-related pathological states.

SUMOylation is described as a posttranslational protein modification (PTM) that is involved in the pathophysiological processes underlying several conditions related to ischemia- and reperfusion-induced damage. Increasing evidence suggests that, under low oxygen levels, SUMOylation might be part of an endogenous mechanism, which is triggered by injury to protect cells within the central nervous system. However, the role of ischemia-induced SUMOylation in the periphery is still unclear. This article summarizes the results of recent studies regarding SUMOylation profiles in several diseases characterized by impaired blood flow to the cardiorenal, gastrointestinal, and respiratory systems. Our review shows that although ischemic injury per se does not always increase SUMOylation levels, as seen in strokes, it seems that in most cases the positive modulation of protein SUMOylation after peripheral ischemia might be a protective mechanism. This complex relationship warrants further investigation, as the role of SUMOylation during hypoxic conditions differs from organ to organ and is still not fully elucidated.

Effects of amyloid-ß on protein SUMOylation and levels of mitochondrial proteins in primary cortical neurons.

Defining the molecular changes that underlie Alzheimer's disease (AD) is an important question in neuroscience. Here, we examined changes in protein SUMOylation, and proteins involved in mitochondrial dynamics, in an in vitro model of AD induced by application of amyloid-ß 1-42 (Aß1-42) to cultured neurons. We observed Aß1-42-induced decreases in global SUMOylation and in levels of the SUMO pathway enzymes SENP3, PIAS1/2, and SAE2. Aß exposure also decreased levels of the mitochondrial fission proteins Drp1 and Mff and increased activation of caspase-3. To examine whether loss of SENP3 is cytoprotective we knocked down SENP3, which partially prevented the Aß1-42-induced increase in caspase-3 activation. Together, these data support the hypothesis that altered SUMOylation may play a role in the mechanisms underlying AD.

SUMO-modifying Huntington's disease.

Small ubiquitin-like modifiers, SUMOs, are proteins that are conjugated to target substrates and regulate their functions in a post-translational modification called SUMOylation. In addition to its physiological roles, SUMOylation has been implicated in several neurodegenerative diseases, such as Alzheimer's, Parkinson's, and Huntington's diseases (HD). HD is a neurodegenerative monogenetic autosomal dominant disorder caused by a mutation in the CAG repeat of the huntingtin (htt) gene, which expresses a mutant Htt protein more susceptible to aggregation and toxicity. Besides Htt, other SUMO ligases, enzymes, mitochondrial and autophagic components are also important for the progression of the disease. Here we review the main aspects of Htt SUMOylation and its role in cellular processes involved in the pathogenesis of HD.

Restraint stress potentiates neuropeptide Y-mediated impairment on spatial memory in rats.

Memory is the ability to store, retrieve and use information that requires a progressive time-dependent stabilization process known as consolidation to be established. The hippocampus is essential for processing all the information that forms memory, especially spatial memory. Neuropeptide Y (NPY) affects memory, so in this study we investigated the participation and recruitment of NPY receptors during spatial memory consolidation in rats. Using the water maze test, we show that NPY (1 pmol) injected into the dorsal hippocampus impaired memory consolidation and that previous restraint stress (30 min) potentiates NPY effects, i.e. further impaired memory consolidation. Using selective antagonists for NPY Y1 and Y2 receptors we demonstrate that both receptors play a key role on spatial memory consolidation. Our data suggest that NPY modulates aversive and adaptive memory formation by NPY receptors activation.

CaV2.2 (N-type) voltage-gated calcium channels are activated by SUMOylation pathways.

SUMOylation is an important post-translational modification process involving covalent attachment of SUMO (Small Ubiquitin-like MOdifier) protein to target proteins. Here, we investigated the potential for SUMO-1 protein to modulate the function of the CaV2.2 (N-type) voltage-gated calcium channel (VGCC), a protein vital for presynaptic neurotransmitter release. Co-expression of SUMO-1, but not the conjugation-deficient mutant SUMO-1ΔGG, increased heterologously-expressed CaV2.2 Ca2+ current density, an effect potentiated by the conjugating enzyme Ubc9. Expression of sentrin-specific protease (SENP)-1 or Ubc9 alone, had no effect on recombinant CaV2.2 channels. Co-expression of SUMO-1 and Ubc9 caused an increase in whole-cell maximal conductance (Gmax) and a hyperpolarizing shift in the midpoint of activation (V1/2). Mutation of all five CaV2.2 lysine residues to arginine within the five highest probability (>65 %) SUMOylation consensus motifs (SCMs) (construct CaV2.2-Δ5KR), produced a loss-of-function mutant. Mutagenesis of selected individual lysine residues identified K394, but not K951, as a key residue for SUMO-1-mediated increase in CaV2.2 Ca2+ current density. In synaptically-coupled superior cervical ganglion (SCG) neurons, SUMO-1 protein was distributed throughout the cell body, axons and dendrites and presumptive presynaptic terminals, whilst SUMO-1ΔGG protein was largely confined to the cell body, in particular, the nucleus. SUMO-1 expression caused increases in paired excitatory postsynaptic potential (EPSP) ratio at short (20-120 ms) inter-stimuli intervals in comparison to SUMO-1ΔGG, consistent with an increase in residual presynaptic Ca2+ current and an increase in release probability of synaptic vesicles. Together, these data provide evidence for CaV2.2 VGCCs as novel targets for SUMOylation pathways.

Guanosine modulates SUMO2/3-ylation in neurons and astrocytes via adenosine receptors.

SUMOylation is a post-translational modification (PTM) whereby members of the Small Ubiquitin-like MOdifier (SUMO) family of proteins are conjugated to lysine residues in target proteins. SUMOylation has been implicated in a wide range of physiological and pathological processes, and much attention has been given to its role in neurodegenerative conditions. Due to its reported role in neuroprotection, pharmacological modulation of SUMOylation represents an attractive potential therapeutic strategy in a number of different brain disorders. However, very few compounds that target the SUMOylation pathway have been identified. Guanosine is an endogenous nucleoside with important neuromodulatory and neuroprotective effects. Experimental evidence has shown that guanosine can modulate different intracellular pathways, including PTMs. In the present study we examined whether guanosine alters global protein SUMOylation. Primary cortical neurons and astrocytes were treated with guanosine at 1, 10, 100, 300, or 500 µM at four time points, 1, 6, 24, or 48 h. We show that guanosine increases global SUMO2/3-ylation in neurons and astrocytes at 1 h at concentrations above 10 µM. The molecular mechanisms involved in this effect were evaluated in neurons. The guanosine-induced increase in global SUMO2/3-ylation was still observed in the presence of dipyridamole, which prevents guanosine internalization, demonstrating an extracellular guanosine-induced effect. Furthermore, the A1 adenosine receptor antagonist DPCPX abolished the guanosine-induced increase in SUMO2/3-ylation. The A2A adenosine receptor antagonist ZM241385 increased SUMOylation per se, but did not alter guanosine-induced SUMOylation, suggesting that guanosine may modulate SUMO2/3-ylation through an A1-A2A receptor interaction. Taken together, this is the first report to show guanosine as a SUMO2/3-ylation enhancer in astrocytes and neurons.

Post-translational modifications of Parkinson's disease-related proteins: Phosphorylation, SUMOylation and Ubiquitination.

Parkinson's disease (PD) is a neurodegenerative disorder characterized by loss of dopaminergic neurons in the nigrostriatal pathway. The etiology of PD remains unclear and most cases are sporadic, however genetic mutations in more than 20 proteins have been shown to cause inherited forms of PD. Many of these proteins are linked to mitochondrial function, defects in which are a central characteristic of PD. Post-translational modifications (PTMs) allow rapid and reversible control over protein function. Largely focussing on mitochondrial dysfunction in PD, here we review findings on the PTMs phosphorylation, SUMOylation and ubiquitination that have been shown to affect PD-related proteins.

2D versus 3D human induced pluripotent stem cell-derived cultures for neurodegenerative disease modelling.

Neurodegenerative diseases, such as Alzheimer's disease (AD), Parkinson's disease (PD), Huntington's disease (HD) and amyotrophic lateral sclerosis (ALS), affect millions of people every year and so far, there are no therapeutic cures available. Even though animal and histological models have been of great aid in understanding disease mechanisms and identifying possible therapeutic strategies, in order to find disease-modifying solutions there is still a critical need for systems that can provide more predictive and physiologically relevant results. One possible avenue is the development of patient-derived models, e.g. by reprogramming patient somatic cells into human induced pluripotent stem cells (hiPSCs), which can then be differentiated into any cell type for modelling. These systems contain key genetic information from the donors, and therefore have enormous potential as tools in the investigation of pathological mechanisms underlying disease phenotype, and progression, as well as in drug testing platforms. hiPSCs have been widely cultured in 2D systems, but in order to mimic human brain complexity, 3D models have been proposed as a more advanced alternative. This review will focus on the use of patient-derived hiPSCs to model AD, PD, HD and ALS. In brief, we will cover the available stem cells, types of 2D and 3D culture systems, existing models for neurodegenerative diseases, obstacles to model these diseases in vitro, and current perspectives in the field.

Sumoylation: Implications for Neurodegenerative Diseases.

The covalent posttranslational modifications of proteins are critical events in signaling cascades that enable cells to efficiently, rapidly and reversibly respond to extracellular stimuli. This is especially important in the CNS where the processes affecting synaptic communication between neurons are highly complex and very tightly regulated. Sumoylation regulates the function and fate of a diverse array of proteins and participates in the complex cell signaling pathways required for cell survival. One of the most complex signaling pathways is synaptic transmission.Correct synaptic function is critical to the working of the brain and its alteration through synaptic plasticity mediates learning, mental disorders and stroke. The investigation of neuronal sumoylation is a new and exciting field and the functional and pathophysiological implications are far-reaching. Sumoylation has already been implicated in a diverse array of neurological disorders. Here we provide an overview of current literature highlighting recent insights into the role of sumoylation in neurodegeneration. In addition we present a brief assessment of drug discovery in the analogous ubiquitin system and extrapolate on the potential for development of novel therapies that might target SUMO-associated mechanisms of neurodegenerative disease.

SUMOylation and calcium signalling: potential roles in the brain and beyond.

Small ubiquitin-like modifier (SUMO) conjugation (or SUMOylation) is a post-translational protein modification implicated in alterations to protein expression, localization and function. Despite a number of nuclear roles for SUMO being well characterized, this process has only started to be explored in relation to membrane proteins, such as ion channels. Calcium ion (Ca2+) signalling is crucial for the normal functioning of cells and is also involved in the pathophysiological mechanisms underlying relevant neurological and cardiovascular diseases. Intracellular Ca2+ levels are tightly regulated; at rest, most Ca2+ is retained in organelles, such as the sarcoplasmic reticulum, or in the extracellular space, whereas depolarization triggers a series of events leading to Ca2+ entry, followed by extrusion and reuptake. The mechanisms that maintain Ca2+ homoeostasis are candidates for modulation at the post-translational level. Here, we review the effects of protein SUMOylation, including Ca2+ channels, their proteome and other proteins associated with Ca2+ signalling, on vital cellular functions, such as neurotransmission within the central nervous system (CNS) and in additional systems, most prominently here, in the cardiac system.