Neuroimmunometabolism: A New Pathological Nexus Underlying Neurodegenerative Disorders.

Neuroimmunometabolism is an emerging field that examines the intersection of immunologic and metabolic cascades in the brain. Neuroinflammatory conditions often involve differential metabolic reprogramming in neuronal and glial cells through their immunometabolic sensors. The impact of such bioenergetic adaptation on general brain function is poorly understood, but this cross-talk becomes increasingly important in neurodegenerative disorders that exhibit reshaping of neuroimmunometabolic pathways. Here we summarize the intrinsic balance of neuroimmunometabolic substrates and sensors in the healthy brain and how their dysregulation can contribute to the pathophysiology of various neurodegenerative disorders. This review also proposes possible avenues for disease management through neuroimmunometabolic profiling and therapeutics to bridge translational gaps and guide future treatment strategies.SIGNIFICANCE STATEMENT Neuroimmunometabolism intersects with neuroinflammation and immunometabolic regulation of neurons and glial cells in the CNS. There is emerging evidence that neuroimmunometabolism plays an essential role in the manifestation of CNS degeneration. This review highlights how neuroimmunometabolic homeostasis is disrupted in various neurodegenerative conditions and could be a target for new therapeutic strategies.

Neuroadaptations and TGF-ß signaling: emerging role in models of neuropsychiatric disorders.

Neuropsychiatric diseases are manifested by maladaptive behavioral plasticity. Despite the greater understanding of the neuroplasticity underlying behavioral adaptations, pinpointing precise cellular mediators has remained elusive. This has stymied the development of pharmacological interventions to combat these disorders both at the level of progression and relapse. With increased knowledge on the putative role of the transforming growth factor (TGF- ß) family of proteins in mediating diverse neuroadaptations, the influence of TGF-ß signaling in regulating maladaptive cellular and behavioral plasticity underlying neuropsychiatric disorders is being increasingly elucidated. The current review is focused on what is currently known about the TGF-ß signaling in the central nervous system in mediating cellular and behavioral plasticity related to neuropsychiatric manifestations.

Neuroadaptations in the dorsal hippocampus underlie cocaine seeking during prolonged abstinence.

Relapse vulnerability in substance use disorder is attributed to persistent cue-induced drug seeking that intensifies (or "incubates") during drug abstinence. Incubated cocaine seeking has been observed in both humans with cocaine use disorder and in preclinical relapse models. This persistent relapse vulnerability is mediated by neuroadaptations in brain regions involved in reward and motivation. The dorsal hippocampus (DH) is involved in context-induced reinstatement of cocaine seeking but the role of the DH in cocaine seeking during prolonged abstinence has not been investigated. Here we found that transforming growth factor-ß (TGF-ß) superfamily member activin A is increased in the DH on abstinence day (AD) 30 but not AD1 following extended-access cocaine self-administration compared to saline controls. Moreover, activin A does not affect cocaine seeking on AD1 but regulates cocaine seeking on AD30 in a bidirectional manner. Next, we found that activin A regulates phosphorylation of NMDA receptor (NMDAR) subunit GluN2B and that GluN2B-containing NMDARs also regulate expression of cocaine seeking on AD30. Activin A and GluN2B-containing NMDARs have both previously been implicated in hippocampal synaptic plasticity. Therefore, we examined synaptic strength in the DH during prolonged abstinence and observed an increase in moderate long-term potentiation (LTP) in cocaine-treated rats compared to saline controls. Lastly, we examined the role of DH projections to the lateral septum (LS), a brain region implicated in cocaine seeking and found that DH projections to the LS govern cocaine seeking on AD30. Taken together, this study demonstrates a role for the DH in relapse behavior following prolonged abstinence from cocaine self-administration.

A role for the endocannabinoid enzymes monoacylglycerol and diacylglycerol lipases in cue-induced cocaine craving following prolonged abstinence.

Following exposure to drugs of abuse, long-term neuroadaptations underlie persistent risk to relapse. Endocannabinoid signaling has been associated with drug-induced neuroadaptations, but the role of lipases that mediate endocannabinoid biosynthesis and metabolism in regulating relapse behaviors following prolonged periods of drug abstinence has not been examined. Here, we investigated how pharmacological manipulation of lipases involved in regulating the expression of the endocannabinoid 2-AG in the nucleus accumbens (NAc) influence cocaine relapse via discrete neuroadaptations. At prolonged abstinence (30 days) from cocaine self-administration, there is an increase in the NAc levels of diacylglycerol lipase (DAGL), the enzyme responsible for the synthesis of the endocannabinoid 2-AG, along with decreased levels of monoacylglycerol lipase (MAGL), which hydrolyzes 2-AG. Since endocannabinoid-mediated behavioral plasticity involves phosphatase dysregulation, we examined the phosphatase calcineurin after 30 days of abstinence and found decreased expression in the NAc, which we demonstrate is regulated through the transcription factor EGR1. Intra-NAc pharmacological manipulation of DAGL and MAGL with inhibitors DO-34 and URB-602, respectively, bidirectionally regulated cue-induced cocaine seeking and altered the phosphostatus of translational initiation factor, eIF2α. Finally, we found that cocaine seeking 30 days after abstinence leads to decreased phosphorylation of eIF2α and reduced expression of its downstream target NPAS4, a protein involved in experience-dependent neuronal plasticity. Together, our findings demonstrate that lipases that regulate 2-AG expression influence transcriptional and translational changes in the NAc related to drug relapse vulnerability.

Trait specific modulatory effects of caffeine exposure on compulsive-like behaviors in a spontaneous mouse model of obsessive-compulsive disorder.

Obsessive-compulsive disorder (OCD) is a psychiatric disorder characterized by recurring intrusive thoughts and repetitive compulsive behaviors, ultimately interfering with their quality of life. The complex heterogeneity of symptom dimensions across OCD patient subgroups impedes diagnosis and treatment. The core and comorbid symptomologies of OCD are thought to be modulated by common environmental exposures such as consumption of the psychostimulant caffeine. The effect of caffeine on the expression of obsessions and compulsions are unexplored. The current study utilized mouse strains (HA) with a spontaneous, predictable, and stable compulsive-like phenotype that have face, predictive, and construct validity for OCD. We demonstrate that an acute high dose (25 mg/kg) of caffeine decreased compulsive-like nest-building behavior in the HA strains in the first hour after injection. However, nest-building scores increased in hours 3, 4, and 5 after administration finally decreasing over a 24 h period. In contrast, a high dose of chronic caffeine (25 mg/kg/d) increased nest-building behavior. Interestingly for compulsive-like digging behavior, acute exposure to a high dose of caffeine decreased the number of marbles buried, while chronic exposure had little effect. An acute high dose of caffeine decreased anxiety-like and motor activity in open field behaviors whereas chronic caffeine administration did not have any overall effect on open field activity. The results, therefore, suggest a complex role of caffeine on compulsive-like, anxiety-like, and locomotor behaviors that is dependent on the duration of exposure.

Allosterism of Nicotinic Acetylcholine Receptors: Therapeutic Potential for Neuroinflammation Underlying Brain Trauma and Degenerative Disorders.

Inflammation is a key physiological phenomenon that can be pervasive when dysregulated. Persistent chronic inflammation precedes several pathophysiological conditions forming one of the critical cellular homeostatic checkpoints. With a steady global surge in inflammatory diseases, it is imperative to delineate underlying mechanisms and design suitable drug molecules targeting the cellular partners that mediate and regulate inflammation. Nicotinic acetylcholine receptors have a confirmed role in influencing inflammatory pathways and have been a subject of scientific scrutiny underlying drug development in recent years. Drugs designed to target allosteric sites on the nicotinic acetylcholine receptors present a unique opportunity to unravel the role of the cholinergic system in regulating and restoring inflammatory homeostasis. Such a therapeutic approach holds promise in treating several inflammatory conditions and diseases with inflammation as an underlying pathology. Here, we briefly describe the potential of cholinergic allosterism and some allosteric modulators as a promising therapeutic option for the treatment of neuroinflammation.

Attenuation of compulsive-like behavior by fluvoxamine in a non-induced mouse model of obsessive-compulsive disorder.

The current study evaluated the role of strain and compulsive trait differences in response to fluvoxamine, a common obsessive-compulsive disorder (OCD) drug, in two different mouse strains (BIG1 and BIG2) with a spontaneous compulsive-like phenotype. For compulsive-like nest-building behavior, dose-dependent attenuation of nesting by fluvoxamine was observed for the BIG1 compulsive-like strain during the first hour after administration. No significant differences were found for the BIG2 strain during the first hour, although a dose-dependent trend similar to that in the BIG1 strain was observed. Fluvoxamine dose dependently decreased the number of marbles buried in both strains 1 h after administration. For anxiety-like behaviors in the open field, no significant drug effects were found for the latency to leave the center and the number of line crossings. Significant strain differences were observed, with the BIG2 strain showing higher anxiety-like behaviors and reduced locomotor activity compared with the BIG1 strain. Consequently, this study adds predictive validity to our mouse model of OCD, whereas the anxiety-like differences between the strains add heterogeneity to our mouse model, similar to the heterogeneity observed in OCD.

Novel psychoplastogen DM506 reduces cue-induced heroin-seeking and inhibits tonic GABA currents in the Prelimbic Cortex.

Opioid use disorder is a major public health crisis that is manifested by persistent drug-seeking behavior and high relapse frequency. Most of the available treatments rely on targeting opioid receptors using small molecules that do not provide sustained symptom alleviation. Psychoplastogens are a novel class of non-opioid drugs that produce rapid and sustained effects on neuronal plasticity, intended to produce therapeutic benefits. Ibogalogs are synthetic derivatives of iboga alkaloids that lack hallucinogenic or adverse side effects. In the current study, we examine the therapeutic potential of DM506, a novel ibogalog lacking any cardiotoxic or hallucinogenic effects, in cue-induced seeking behavior following heroin self-administration. At a single systemic dose of 40 mg/kg, DM506 significantly decreased cue-induced seeking in both male and female rats at abstinence day 1 (AD1) following heroin self-administration. Upon re-testing for cue-induced seeking at AD14, we found that males receiving DM506 continued to show decreased cue-induced seeking, an effect not observed in females. Since there is evidence of psychedelics influencing tonic GABA currents, and opioid and psychoplastogen-mediated neuroadaptations in the medial prefrontal cortex (PrL) underlying its functional effects, we performed patch-clamp recordings on PrL slices of drug-naïve rats with an acute application or chronic incubation with DM506. Tonic GABA current was decreased in slices incubated with DM506 for 2 h. qPCR analysis did not reveal any differences in the mRNA levels of GABAA receptor α and δ subunits at AD14 in heroin and saline self-administered animals that received vehicle or DM506 at AD1. Overall, our data indicate that DM506 attenuates cue-induced heroin seeking and inhibits tonic GABA current in the prelimbic cortex.

Sex differences in acute delta-9-tetrahydrocannabinol (Δ9-THC) response and tolerance as a function of mouse strain.

Cannabinoids are increasingly used to alleviate pain; however, tolerance to their antinociceptive effects, including those of delta-9-tetrahydrocannabinol (Δ9-THC), may limit their therapeutic utility. With more women than men using medical cannabis for pain relief, it is crucial to understand how sex influences cannabinoid-mediated antinociception and tolerance. Though studies in rats consistently find females are more sensitive to the acute antinociceptive effects of cannabinoids, our work with mice consistently finds the converse. The present study examined whether our observed sex differences in Δ9-THC-induced antinociception and tolerance are consistent across multiple mouse strains or are strain-dependent. Male and female C57BL/6J (B6), DBA/2, AKR, and CBA/J mice were assessed for differences in acute Δ9-THC-induced antinociception and hypothermia prior to and following seven days of once-daily Δ9-THC administration. Consistent with our previous findings, male B6 mice were more sensitive to the acute antinociceptive effects of Δ9-THC than female littermates, an effect which dissipated with age. B6 males had decreased cannabinoid expression in the PAG compared to females. While DBA and CBA female mice showed increased Δ9-THC-antinociception compared to male littermates at 30 and 10 mg/kg Δ9-THC, respectively, these differences were less pronounced at higher doses, revealing that dose of Δ9-THC may also be important. Overall, CBA mice were more sensitive to Δ9-THC-induced antinociception while AKR mice were less responsive. These studies highlight the therapeutic potential of Δ9-THC in pain management and underscore the importance of considering not only Δ9-THC dose as a function of sex, but potentially genetic differences when evaluating their clinical utility.

The ubiquitin-proteasome system and learning-dependent synaptic plasticity - A 10 year update.

Over 25 years ago, a seminal paper demonstrated that the ubiquitin-proteasome system (UPS) was involved in activity-dependent synaptic plasticity. Interest in this topic began to expand around 2008 following another seminal paper showing that UPS-mediated protein degradation controlled the "destabilization" of memories following retrieval, though we remained with only a basic understanding of how the UPS regulated activity- and learning-dependent synaptic plasticity. However, over the last 10 years there has been an explosion of papers on this topic that has significantly changed our understanding of how ubiquitin-proteasome signaling regulates synaptic plasticity and memory formation. Importantly, we now know that the UPS controls much more than protein degradation, is involved in plasticity underlying drugs of abuse and that there are significant sex differences in how ubiquitin-proteasome signaling is used for memory storage processes. Here, we aim to provide a critical 10-year update on the role of ubiquitin-proteasome signaling in synaptic plasticity and memory formation, including updated cellular models of how ubiquitin-proteasome activity could be regulating learning-dependent synaptic plasticity in the brain.

Mechanisms of cannabinoid tolerance.

Cannabis has been used recreationally and medically for centuries, yet research into understanding the mechanisms of its therapeutic effects has only recently garnered more attention. There is evidence to support the use of cannabinoids for the treatment of chronic pain, muscle spasticity, nausea and vomiting due to chemotherapy, improving weight gain in HIV-related cachexia, emesis, sleep disorders, managing symptoms in Tourette syndrome, and patient-reported muscle spasticity from multiple sclerosis. However, tolerance and the risk for cannabis use disorder are two significant disadvantages for cannabinoid-based therapies in humans. Recent work has revealed prominent sex differences in the acute response and tolerance to cannabinoids in both humans and animal models. This review will discuss evidence demonstrating cannabinoid tolerance in rodents, non-human primates, and humans and our current understanding of the neuroadaptations occurring at the cannabinoid type 1 receptor (CB1R) that are responsible tolerance. CB1R expression is downregulated in tolerant animals and humans while there is strong evidence of CB1R desensitization in cannabinoid tolerant rodent models. Throughout the review, critical knowledge gaps are indicated and discussed, such as the lack of a neuroimaging probe to assess CB1R desensitization in humans. The review discusses the intracellular signaling pathways that are responsible for mediating CB1R desensitization and downregulation including the action of G protein-coupled receptor kinases, ß-arrestin2 recruitment, c-Jun N-terminal kinases, protein kinase A, and the intracellular trafficking of CB1R. Finally, the review discusses approaches to reduce cannabinoid tolerance in humans based on our current understanding of the neuroadaptations and mechanisms responsible for this process.

Postpartum scarcity-adversity inflicts sex-specific cerebellar adaptations and reward behaviors in adolescence.

Early life adversity in the form of poor postnatal care is a major developmental stressor impacting behavior later in life. Previous studies have shown the impact of early life stress on neurobehavioral abnormalities. Specifically, research has demonstrated how limited bedding and nesting (LBN) materials can cause behavioral deficits in adulthood. There is, however, a limited understanding of how LBN influences sex-specific neurobehavioral adaptation in adolescence, a developmental stage susceptible to psychiatric diseases including substance use disorder. LBN and stress-naive c57BL/6 adolescent male and female mouse offspring were tested for a battery of behaviors including open field, novel object recognition, elevated plus maze, social preference, and morphine-induced conditioned place preference. There was a significant sex-specific deficit in social preference in male mice exposed to LBN compared to stress-naïve counterparts and both LBN males and females had a higher preference towards the drug-paired chamber in the morphine-induced conditioned place preference test. These behavioral deficits were concomitant with sex-specific increases in the transcription factor, Klf9 in the deep cerebellar nuclei (DCN) of males. Further, mRNA levels of the circadian gene Bmal1, which is known to be transcriptionally regulated by Klf9, were decreased in the DCN. Since Bmal1 has recently been implicated in extracellular matrix modulation, we examined perineuronal nets (PNN) and observed depleted PNN in the DCN of males but not female LBN mice. Overall, we provide a novel understanding of how postpartum adversity impinges on the cerebellar extracellular matrix homeostasis, likely, through disruption of the circadian axis by Klf9 that might underlie sex-specific behavioral adaptations in adolescence.

Modeling and simulation of high energy density lithium-ion battery for multiple fault detection.

Lithium-ion battery, a high energy density storage device has extensive applications in electrical and electronic gadgets, computers, hybrid electric vehicles, and electric vehicles. This paper presents multiple fault detection of lithium-ion battery using two non-linear Kalman filters. A discrete non-linear mathematical model of lithium ion battery has been developed and Unscented Kalman filter (UKF) is employed to estimate the model parameter. Occurrences of multiple faults such as over-charge, over-discharge and short circuit faults between inter cell power batteries, affects the parameter variation of system model. Parallel combinations of some UKF (bank of filters) compare the model parameter variation between the normal and faulty situation and generates residual signal indicating different fault. Simulation results of multiple numbers of statistical tests have been performed for residual based fault diagnosis and threshold calculation. The performance of UKF is then compared with Extended Kalman filter (EKF) with same battery model and fault scenario. The simulation result proves that UKF model responses better and quicker than that of EKF for fault diagnosis.

Histone H3 dopaminylation in ventral tegmental area underlies heroin-induced transcriptional and behavioral plasticity in male rats.

Persistent transcriptional events in ventral tegmental area (VTA) and other reward relevant brain regions contribute to enduring behavioral adaptations that characterize substance use disorder. Recent data from our laboratory indicate that aberrant accumulation of the newly discovered histone post-translational modification (PTM), H3 dopaminylation at glutamine 5 (H3Q5dop), contributes significantly to cocaine-seeking behavior following prolonged periods of abstinence. It remained unclear, however, whether this modification is important for relapse vulnerability in the context of other drugs of abuse, such as opioids. Here, we showed that H3Q5dop plays a critical role in heroin-mediated transcriptional plasticity in midbrain regions, particularly the VTA. In rats undergoing abstinence from heroin self-administration (SA), we found acute and persistent accumulation of H3Q5dop in VTA. Attenuation of H3Q5dop during abstinence induced persistent changes in gene expression programs associated with neuronal signaling and dopaminergic function in heroin abstinence and led to reduced heroin-seeking behavior. Interestingly, the observed changes in molecular pathways after heroin SA showed significant yet reversed overlap with the same genes altered in cocaine SA. These findings establish an essential role for H3Q5dop, and its downstream transcriptional consequences, in heroin-induced functional plasticity in VTA.

EGR3 regulates opioid-related nociception and motivation in male rats.

Chronic pain can be a debilitating condition, leading to profound changes in nearly every aspect of life. However, the reliance on opioids such as oxycodone for pain management is thought to initiate dependence and addiction liability. The neurobiological intersection at which opioids relieve pain and possibly transition to addiction is poorly understood. Using RNA sequencing pathway analysis in rats with complete Freund's adjuvant (CFA)-induced chronic inflammation, we found that the transcriptional signatures in the medial prefrontal cortex (mPFC; a brain region where pain and reward signals integrate) elicited by CFA in combination with oxycodone differed from those elicited by CFA or oxycodone alone. However, the expression of Egr3 was augmented in all animals receiving oxycodone. Furthermore, virus-mediated overexpression of EGR3 in the mPFC increased mechanical pain relief but not the affective aspect of pain in animals receiving oxycodone, whereas pharmacological inhibition of EGR3 via NFAT attenuated mechanical pain relief. Egr3 overexpression also increased the motivation to obtain oxycodone infusions in a progressive ratio test without altering the acquisition or maintenance of oxycodone self-administration. Taken together, these data suggest that EGR3 in the mPFC is at the intersection of nociceptive and addictive-like behaviors.

Bidirectional Behavioral Selection in Mice: A Novel Pre-clinical Approach to Examining Compulsivity.

Obsessive-compulsive disorder (OCD) and related disorders (OCRD) is one of the most prevalent neuropsychiatric disorders with no definitive etiology. The pathophysiological attributes of OCD are driven by a multitude of factors that involve polygenic mechanisms, gender, neurochemistry, physiological status, environmental exposures and complex interactions among these factors. Such complex intertwining of contributing factors imparts clinical heterogeneity to the disorder making it challenging for therapeutic intervention. Mouse strains selected for excessive levels of nest- building behavior exhibit a spontaneous, stable and predictable compulsive-like behavioral phenotype. These compulsive-like mice exhibit heterogeneity in expression of compulsive-like and other adjunct behaviors that might serve as a valuable animal equivalent for examining the interactions of genetics, sex and environmental factors in influencing the pathophysiology of OCD. The current review summarizes the existing findings on the compulsive-like mice that bolster their face, construct and predictive validity for studying various dimensions of compulsive and associated behaviors often reported in clinical OCD and OCRD.

Sex-Specific Role for Egr3 in Nucleus Accumbens D2-Medium Spiny Neurons Following Long-Term Abstinence From Cocaine Self-administration.

BACKGROUND: We previously showed that the transcription factor Egr3 (early growth response 3) is oppositely regulated in nucleus accumbens (NAc) cell subtypes 24 hours following cocaine exposure and bidirectionally mediates cocaine-related behaviors in male rodents. Overexpressing Egr3 in D2 receptor-containing medium spiny neurons (D2-MSNs) before drug exposure reduces the rewarding and psychomotor sensitization effects of cocaine. However, it is unknown if Egr3 plays a role in long-term neuroadaptations in the NAc and relapse to cocaine seeking. METHODS: We measured EGR3 protein levels in the NAc following 20 days of forced abstinence from intravenous cocaine self-administration in 10-week-old Sprague Dawley rats and C57BL/6 mice. In 8- to 10-week-old A2A-Cre mice, we used virally mediated Egr3 overexpression in NAc D2-MSNs to test the role of Egr3 on operant responding during seeking, extinction, and drug-induced reinstatement of cocaine self-administration. To evaluate if Egr3 contributed to sex differences to cocaine relapse, we conducted these procedures in both male and female rodents. RESULTS: We found that EGR3 expression was reduced only in female rodents after 20 days of forced abstinence. Additionally, we showed that our self-administration paradigm in mice recapitulated the sex differences in cocaine intake and relapse demonstrated in humans and rats. Finally, whereas Egr3 overexpression in D2-MSNs during forced abstinence facilitated extinction and blunted drug-induced reinstatement in female mice, it had the opposite effect in male mice. CONCLUSIONS: We showed that the immediate early gene Egr3 has long-term effects on drug-related behaviors. Our work suggests that changes in Egr3 expression in D2-MSNs contributes to sex differences in cocaine relapse.

Dopaminylation of histone H3 in ventral tegmental area regulates cocaine seeking.

Vulnerability to relapse during periods of attempted abstinence from cocaine use is hypothesized to result from the rewiring of brain reward circuitries, particularly ventral tegmental area (VTA) dopamine neurons. How cocaine exposures act on midbrain dopamine neurons to precipitate addiction-relevant changes in gene expression is unclear. We found that histone H3 glutamine 5 dopaminylation (H3Q5dop) plays a critical role in cocaine-induced transcriptional plasticity in the midbrain. Rats undergoing withdrawal from cocaine showed an accumulation of H3Q5dop in the VTA. By reducing H3Q5dop in the VTA during withdrawal, we reversed cocaine-mediated gene expression changes, attenuated dopamine release in the nucleus accumbens, and reduced cocaine-seeking behavior. These findings establish a neurotransmission-independent role for nuclear dopamine in relapse-related transcriptional plasticity in the VTA.

Complex interaction of dietary fat and Alaskan bog blueberry supplementation influences manganese mediated neurotoxicity and behavioral impairments.

Dietary fat modulates neuronal health and contributes to age-related nervous system disorders. However, the complex interaction between dietary fat and supplementation and its consequences on neurotoxic pathophysiology has been sparsely explored. The indigenous Alaskan bog blueberry (BB), Vaccinum uliginosum, is known to have anti-inflammatory properties, mostly attributed to its rich polyphenolic content. Here, we evaluate the interplay between dietary fat and BB supplementation on sub-chronic manganese (Mn) exposure that inflicts neurotoxicity and behavioral impairments. In both low-fat and normal-fat diets, BB supplementation attenuated the behavioral and the molecular hallmarks of Mn-induced neurotoxicity. On the contrary, a high-fat diet was found to exacerbate these Mn-induced pathological features. Furthermore, BB supplementation failed to recover the behavioral deficits in mice subjected to a high fat diet in Mn-treated mice. Overall, our results demonstrate the importance of including a dietary regimen comprised of polyphenolic rich supplements with low-fat content in combating age-related neurodegenerative disorders.

Genetic Silencing of Fatty Acid Desaturases Modulates α-Synuclein Toxicity and Neuronal Loss in Parkinson-Like Models of C. elegans.

The molecular basis of Parkinson's disease (PD) is currently unknown. There is increasing evidence that fat metabolism is at the crossroad of key molecular pathways associated with the pathophysiology of PD. Fatty acid desaturases catalyze synthesis of saturated fatty acids from monounsaturated fatty acids thereby mediating several cellular mechanisms that are associated with diseases including cancer and metabolic disorders. The role of desaturases in modulating age-related neurodegenerative manifestations such as PD is poorly understood. Here, we investigated the effect of silencing Δ9 desaturase enzyme encoding fat-5 and fat-7 genes which are known to reduce fat content, on α-synuclein expression, neuronal morphology and dopamine-related behaviors in transgenic PD-like models of Caenorhabditis elegans (C. elegans). The silencing of the fat-5 and fat-7 genes rescued both degeneration of dopamine neurons and deficits in dopamine-dependent behaviors, including basal slowing and ethanol avoidance in worm models of PD. Similarly, silencing of these genes also decreased the formation of protein aggregates in a nematode model of PD expressing α-synuclein in the body wall muscles and rescued deficits in resistance to heat and osmotic stress. On the contrary, silencing of nhr-49 and tub-1 genes that are known to increase total fat content did not alter behavioral and pathological endpoints in the PD worm strains. Interestingly, the genetic manipulation of all four selected genes resulted in differential fat levels in the PD models without having significant effect on the lifespan, further indicating a complex fat homeostasis unique to neurodegenerative pathophysiology. Overall, we provide a comprehensive understanding of how Δ9 desaturase can alter PD-like pathology due to environmental exposures and proteotoxic stress, suggesting new avenues in deciphering the disease etiology and possible therapeutic targets.