Metabolic dysregulation in Huntington's disease: Neuronal and glial perspectives.

Huntington's disease (HD) is an autosomal dominant neurodegenerative disorder caused by a mutant huntingtin protein with an abnormal CAG/polyQ expansion in the N-terminus of HTT exon 1. HD is characterized by progressive neurodegeneration and metabolic abnormalities, particularly in the brain, which accounts for approximately 20 % of the body's resting metabolic rate. Dysregulation of energy homeostasis in HD includes impaired glucose transporters, abnormal functions of glycolytic enzymes, changes in tricarboxylic acid (TCA) cycle activity and enzyme expression in the basal ganglia and cortical regions of both HD mouse models and HD patients. However, current understanding of brain cell behavior during energy dysregulation and its impact on neuron-glia crosstalk in HD remains limited. This review provides a comprehensive summary of the current understanding of the differences in glucose metabolism between neurons and glial cells in HD and how these differences contribute to disease development compared with normal conditions. We also discuss the potential impact of metabolic shifts on neuron-glia communication in HD. A deeper understanding of these metabolic alterations may reveal potential therapeutic targets for future drug development.

PIAS1 S510G variant acts as a genetic modifier of spinocerebellar ataxia type 3 by selectively impairing mutant ataxin-3 proteostasis.

Dysregulated protein homeostasis, characterized by abnormal protein accumulation and aggregation, is a key contributor to the progression of neurodegenerative disorders such as Huntington's disease and spinocerebellar ataxia type 3 (SCA3). Previous studies have identified PIAS1 gene variants in patients with late-onset SCA3 and Huntington's disease. This study aims to elucidate the role of PIAS1 and its S510G variant in modulating the pathogenic mechanisms of SCA3. Through in vitro biochemical analyses and in vivo assays, we demonstrate that PIAS1 stabilizes both wild-type and mutant ataxin-3 (ATXN3). The PIAS1 S510G variant, however, selectively reduces the stability and SUMOylation of mutant ATXN3, thereby decreasing its aggregation and toxicity while maintaining the stability of wild-type ATXN3. This effect is mediated by a weakened interaction with the SUMO-conjugating enzyme UBC9 in the presence of mutant ATXN3. In Drosophila models, downregulation of dPIAS1 resulted in reduced levels of mutant ATXN3 and alleviated associated phenotypes, including retinal degeneration and motor dysfunction. Our findings suggest that the PIAS1 S510G variant acts as a genetic modifier of SCA3, highlighting the potential of targeting SUMOylation as a therapeutic strategy for this disease.

Equilibrative nucleoside transporter 3 supports microglial functions and protects against the progression of Huntington's disease in the mouse model.

Huntington's disease (HD) is a hereditary neurodegenerative disorder characterized by involuntary movements, cognitive deficits, and psychiatric symptoms. Currently, there is no cure, and only limited treatments are available to manage the symptoms and to slow down the disease's progression. The molecular and cellular mechanisms of HD's pathogenesis are complex, involving immune cell activation, altered protein turnover, and disturbance in brain energy homeostasis. Microglia have been known to play a dual role in HD, contributing to neurodegeneration through inflammation but also enacting neuroprotective effects by clearing mHTT aggregates. However, little is known about the contribution of microglial metabolism to HD progression. This study explores the impact of a microglial metabolite transporter, equilibrative nucleoside transporter 3 (ENT3), in HD. Known as a lysosomal membrane transporter protein, ENT3 is highly enriched in microglia, with its expression correlated with HD severity. Using the R6/2 ENT3-/- mouse model, we found that the deletion of ENT3 increases microglia numbers yet worsens HD progression, leading to mHTT accumulation, cell death, and disturbed energy metabolism. These results suggest that the delicate balance between microglial metabolism and function is crucial for maintaining brain homeostasis and that ENT3 has a protective role in ameliorating neurodegenerative processes.

Anticonvulsant effect of equilibrative nucleoside transporters 1 inhibitor in a mouse model of Dravet syndrome.

There are limited therapeutic options for patients with Dravet syndrome (DS). The equilibrative nucleoside transporters 1 (ENT1) mediate both the influx and efflux of adenosine across the cell membrane exerted beneficial effects in the treatment of epilepsy. This study aimed to evaluate the anticonvulsant effect of the ENT1 inhibitor in an animal model of DS (Scn1aE1099X/+ mice). J7 (5 mg/kg) treatment was efficacious in elevating seizure threshold in Scn1aE1099X/+ mice after hyperthermia exposure. Moreover, the J7 treatment significantly reduced the frequency of spontaneous excitatory post-synaptic currents (sEPSCs, ~35% reduction) without affecting the amplitude in dentate gyrus (DG) granule cells. Pretreatment with the adenosine A1 receptor (A1R) antagonist, DPCPX, abolished the J7 effects on sEPSCs. These observations suggest that the J7 shows an anticonvulsant effect in hyperthermia-induced seizures in Scn1aE1099X/+ mice. This effect possibly acts on presynaptic A1R-mediated signaling modulation in granule cells.

Galectin-3 aggravates microglial activation and tau transmission in tauopathy.

Alzheimer's disease is characterized by the accumulation of amyloid-ß plaques, aggregation of hyperphosphorylated tau (pTau), and microglia activation. Galectin-3 (Gal3) is a ß-galactoside-binding protein that has been implicated in amyloid pathology. Its role in tauopathy remains enigmatic. Here, we showed that Gal3 was upregulated in the microglia of humans and mice with tauopathy. pTau triggered the release of Gal3 from human induced pluripotent stem cell-derived microglia in both its free and extracellular vesicular-associated (EV-associated) forms. Both forms of Gal3 increased the accumulation of pathogenic tau in recipient cells. Binding of Gal3 to pTau greatly enhanced tau fibrillation. Besides Gal3, pTau was sorted into EVs for transmission. Moreover, pTau markedly enhanced the number of EVs released by iMGL in a Gal3-dependent manner, suggesting a role of Gal3 in biogenesis of EVs. Single-cell RNA-Seq analysis of the hippocampus of a mouse model of tauopathy (THY-Tau22) revealed a group of pathogenic tau-evoked, Gal3-associated microglia with altered cellular machineries implicated in neurodegeneration, including enhanced immune and inflammatory responses. Genetic removal of Gal3 in THY-Tau22 mice suppressed microglia activation, reduced the level of pTau and synaptic loss in neurons, and rescued memory impairment. Collectively, Gal3 is a potential therapeutic target for tauopathy.

The Impact of Dysregulated microRNA Biogenesis Machinery and microRNA Sorting on Neurodegenerative Diseases.

MicroRNAs (miRNAs) are 22-nucleotide noncoding RNAs involved in the differentiation, development, and function of cells in the body by targeting the 3'- untranslated regions (UTR) of mRNAs for degradation or translational inhibition. miRNAs not only affect gene expression inside the cells but also, when sorted into exosomes, systemically mediate the communication between different types of cells. Neurodegenerative diseases (NDs) are age-associated, chronic neurological diseases characterized by the aggregation of misfolded proteins, which results in the progressive degeneration of selected neuronal population(s). The dysregulation of biogenesis and/or sorting of miRNAs into exosomes was reported in several NDs, including Huntington's disease (HD), Parkinson's disease (PD), amyotrophic lateral sclerosis (ALS), and Alzheimer's disease (AD). Many studies support the possible roles of dysregulated miRNAs in NDs as biomarkers and therapeutic treatments. Understanding the molecular mechanisms underlying the dysregulated miRNAs in NDs is therefore timely and important for the development of diagnostic and therapeutic interventions. In this review, we focus on the dysregulated miRNA machinery and the role of RNA-binding proteins (RBPs) in NDs. The tools that are available to identify the target miRNA-mRNA axes in NDs in an unbiased manner are also discussed.

Deletion of equilibrative nucleoside transporter 2 disturbs energy metabolism and exacerbates disease progression in an experimental model of Huntington's disease.

Huntington's disease (HD) is an autosomal dominant neurodegenerative disease, characterized by motor dysfunction and abnormal energy metabolism. Equilibrative nucleoside transporter 1 (ENT1) and ENT2 are the major nucleoside transporters in cellular plasma membrane of the brain. Yet, unlike ENT1 whose function has been better investigated in HD, the role of ENT2 in HD remains unclear. The present study aimed to investigate the impacts of ENT2 deletion on HD using a well-characterized mouse model (R6/2). Microarray analysis, quantitative real-time polymerase chain reaction, and immunostaining of ENT2 in postmortem human brain tissues were conducted. R6/2 mice with or without genetic deletion of ENT2 were generated. Motor functions, including rotarod performance and limb-clasping test, were examined at the age of 7 to 12 weeks. Biochemical changes were evaluated by immunofluorescence staining and immunoblotting at the age of 12 to 13 weeks. In regard to energy metabolism, levels of striatal metabolites were determined by liquid chromatography coupled with the fluorescence detector or quadrupole time-of-flight mass spectrometer. Mitochondrial bioenergetics was assessed by the Seahorse assay. The results showed that ENT2 protein was detected in the neurons and astrocytes of human brains and the levels in the postmortem brain tended to be higher in patients with HD. In mice, ENT2 deletion did not alter the phenotype of the non-HD controls. Yet, ENT2 deletion deteriorated motor function and increased the number of aggregated mutant huntingtin in the striatum of R6/2 mice. Notably, disturbed energy metabolism with decreased ATP level and increased AMP/ ATP ratio was observed in R6/2-Ent2-/- mice, compared with R6/2-Ent2+/+ mice, resulting in the activation of AMPK in the late disease stage. Furthermore, ENT2 deletion reduced the NAD+/NADH ratio and impaired mitochondrial respiration in the striatum of R6/2 mice. Taken together, these findings indicate the crucial role of ENT2 in energy homeostasis, in which ENT2 deletion further impairs mitochondrial bioenergetics and deteriorates motor function in R6/2 mice.

Equilibrative Nucleoside Transporter 1 is a Target to Modulate Neuroinflammation and Improve Functional Recovery in Mice with Spinal Cord Injury.

Neuroinflammation plays a critical role in the neurological recovery of spinal cord injury (SCI). Adenosine can modulate neuroinflammation, whose uptake is mediated by nucleoside transporters. This study aimed to investigate the roles of equilibrative nucleoside transporter 1 (Ent1) in the inflammatory responses and functional recovery of SCI. Spinal cord contusion at the T10 dorsal portion was induced in mice to cause partial paralysis of the hindlimbs. Genetic deletion and pharmacological inhibition of Ent1 were used to evaluate the role of Ent1 in SCI. The outcomes were evaluated in terms of the Basso Mouse Scale (BMS), gait analysis, astrogliosis, microgliosis, and cytokine levels on day 14 post-injury. As a result, Ent1 deletion reduced neuroinflammation and improved the BMS score (4.88 ± 0.35 in Ent1-/- vs. 3.78 ± 1.09 in Ent1+/+) and stride length (3.74 ± 0.48 cm in Ent1-/- vs. 2.82 ± 0.78 cm in Ent1+/+) of mice with SCI. Along with the reduced lesion size, more preserved neurons were identified in the perilesional area of mice with Ent1 deletion (102 ± 23 in Ent1-/- vs. 73 ± 10 in Ent1+/+). The results of pharmacological inhibition were consistent with the findings of genetic deletion. Moreover, Ent1 inhibition decreased the protein level of complement 3 (an A1 marker), but increased the levels of S100 calcium-binding protein a10 (an A2 marker) and transforming growth factor-ß, without changing the levels of inducible nitric oxide synthase (a M1 marker) and arginase 1 (a M2 marker) at the injured site. These findings indicate the important role of Ent1 in the pathogenesis and treatment of SCI.

Roles of Siglecs in neurodegenerative diseases.

Microglia are resident myeloid cells in the central nervous system (CNS) with a unique developmental origin, playing essential roles in developing and maintaining the CNS environment. Recent studies have revealed the involvement of microglia in neurodegenerative diseases, such as Alzheimer's disease, through the modulation of neuroinflammation. Several members of the Siglec family of sialic acid recognition proteins are expressed on microglia. Since the discovery of the genetic association between a polymorphism in the CD33 gene and late-onset Alzheimer's disease, significant efforts have been made to elucidate the molecular mechanism underlying the association between the polymorphism and Alzheimer's disease. Furthermore, recent studies have revealed additional potential associations between Siglecs and Alzheimer's disease, implying that the reduced signal from inhibitory Siglec may have an overall protective effect in lowering the disease risk. Evidences suggesting the involvement of Siglecs in other neurodegenerative diseases are also emerging. These findings could help us predict the roles of Siglecs in other neurodegenerative diseases. However, little is known about the functionally relevant Siglec ligands in the brain, which represents a new frontier. Understanding how microglial Siglecs and their ligands in CNS contribute to the regulation of CNS homeostasis and pathogenesis of neurodegenerative diseases may provide us with a new avenue for disease prevention and intervention.

Exploring the role of hub and network dysfunction in brain connectomes of schizophrenia using functional magnetic resonance imaging.

Introduction: Pathophysiological etiology of schizophrenia remains unclear due to the heterogeneous nature of its biological and clinical manifestations. Dysfunctional communication among large-scale brain networks and hub nodes have been reported. In this study, an exploratory approach was adopted to evaluate the dysfunctional connectome of brain in schizophrenia. Methods: Two hundred adult individuals with schizophrenia and 200 healthy controls were recruited from Taipei Veterans General Hospital. All subjects received functional magnetic resonance imaging (fMRI) scanning. Functional connectivity (FC) between parcellated brain regions were obtained. Pair-wise brain regions with significantly different functional connectivity among the two groups were identified and further analyzed for their concurrent ratio of connectomic differences with another solitary brain region (single-FC dysfunction) or dynamically interconnected brain network (network-FC dysfunction). Results: The right thalamus had the highest number of significantly different pair-wise functional connectivity between schizophrenia and control groups, followed by the left thalamus and the right middle frontal gyrus. For individual brain regions, dysfunctional single-FCs and network-FCs could be found concurrently. Dysfunctional single-FCs distributed extensively in the whole brain of schizophrenia patients, but overlapped in similar groups of brain nodes. A dysfunctional module could be formed, with thalamus being the key dysfunctional hub. Discussion: The thalamus can be a critical hub in the brain that its dysfunctional connectome with other brain regions is significant in schizophrenia patients. Interconnections between dysfunctional FCs for individual brain regions may provide future guide to identify critical brain pathology associated with schizophrenia.

TRAX Provides Neuroprotection for Huntington's Disease Via Modulating a Novel Subset of MicroRNAs.

BACKGROUND: Huntington's disease (HD) is a neurodegenerative disease caused by CAG-repeat expansions (>36) in exon 1 of HTT, which dysregulates multiple cellular machineries. Translin-associated protein X (TRAX) is a scaffold protein with diverse functions, including suppressing the microRNA (miRNA)-mediated silencing by degrading pre-miRNA. To date, the role of TRAX in neurodegenerative diseases remains unknown. OBJECTIVES: We delineated the role of TRAX upregulation during HD progression. METHODS: Expression of TRAX in the brains of humans and three mouse models with HD were analyzed by immunohistochemistry staining, western blot, and quantitative reverse transcription-polymerase chain reaction. Adeno-associated viruses harboring TRAX short hairpin RNA were intrastriatally injected into HD mice to downregulate TRAX. HD-like symptoms were analyzed by behavioral and biochemical assessments. The miRNA-sequencing and RNA-sequencing analyses were used to identify the TRAX- regulated miRNA-messenger RNA (mRNA) axis during HD progression. The identified gene targets were validated biochemically in mouse and human striatal cells. RESULTS: We discovered that TRAX was upregulated in the brains of HD patients and three HD mouse models. Downregulation of TRAX enhanced 83 miRNAs (including miR-330-3p, miR-496a-3p) and subsequently changed the corresponding mRNA networks critical for HD pathogenesis (eg, DARPP-32 and brain-derived neurotrophic factor). Disruption of the TRAX-mediated miRNA-mRNA axis accelerated the progression of HD-like symptoms, including the degeneration of motor function, accumulation of mHTT aggregates, and shortened neurite outgrowth. CONCLUSIONS: We demonstrated that TRAX upregulation is authentic and protective in HD. Our study provides a novel layer of regulation for HD pathogenesis and may lead to the development of new therapeutic strategies for HD. © 2022 International Parkinson and Movement Disorder Society.

Calpain-2 Mediates MBNL2 Degradation and a Developmental RNA Processing Program in Neurodegeneration.

Increasing loss of structure and function of neurons and decline in cognitive function is commonly seen during the progression of neurologic diseases, although the causes and initial symptoms of individual diseases are distinct. This observation suggests a convergence of common degenerative features. In myotonic dystrophy type 1 (DM1), the expression of expanded CUG RNA induces neurotransmission dysfunction before axon and dendrite degeneration and reduced MBNL2 expression associated with aberrant alternative splicing. The role of loss of function of MBNL2 in the pathogenesis of neurodegeneration and the causal mechanism of neurodegeneration-reduced expression of MBNL2 remain elusive. Here, we show that increased MBNL2 expression is associated with neuronal maturation and required for neuronal morphogenesis and the fetal to adult developmental transition of RNA processing. Neurodegenerative conditions including NMDA receptor (NMDAR)-mediated excitotoxicity and dysregulated calcium homeostasis triggered nuclear translocation of calpain-2, thus resulting in MBNL2 degradation and reversal of MBNL2-regulated RNA processing to developmental patterns. Nuclear expression of calpain-2 resembled its developmental pattern and was associated with MBNL2 degradation. Knock-down of calpain-2 expression or inhibition of calpain-2 nuclear translocation prevented neurodegeneration-reduced MBNL2 expression and dysregulated RNA processing. Increased calpain-2 nuclear translocation associated with reduced MBNL2 expression and aberrant RNA processing occurred in models for DM1 and Alzheimer's disease (AD) including EpA960/CaMKII-Cre mice of either sex and female APP/PS1 and THY-Tau22 mice. Our results identify a regulatory mechanism for MBNL2 downregulation and suggest that calpain-2-mediated MBNL2 degradation accompanied by re-induction of a developmental RNA processing program may be a converging pathway to neurodegeneration.SIGNIFICANCE STATEMENT Neurologic diseases share many features during disease progression, such as cognitive decline and brain atrophy, which suggests a common pathway for developing degenerative features. Here, we show that the neurodegenerative conditions glutamate-induced excitotoxicity and dysregulated calcium homeostasis induced translocation of the cysteine protease calpain-2 into the nucleus, resulting in MBNL2 degradation and reversal of MBNL2-regulated RNA processing to an embryonic pattern. Knock-down or inhibition of nuclear translocation of calpain-2 prevented MBNL2 degradation and maintained MBNL2-regulated RNA processing in the adult pattern. Models of myotonic dystrophy and Alzheimer's disease (AD) also showed calpain-2-mediated MBNL2 degradation and a developmental RNA processing program. Our studies suggest MBNL2 function disrupted by calpain-2 as a common pathway, thus providing an alternative therapeutic strategy for neurodegeneration.

N6-substituated adenosine analog J4 attenuates anxiety-like behaviors in mice.

RATIONALE: Withdrawal from chronic alcohol exposure produces various physical and mental withdrawal symptoms. Activation of adenosine receptors is known to inhibit withdrawal-induced excitation. However, limited studies investigate how adenosine analogs may prove helpful tools to alleviate alcohol withdrawal-related affective behaviors. OBJECTIVES: This study aimed to investigate the effects of J4 compared with saline using the mice vapor or voluntary ethanol drinking model on behavioral endpoints representing ethanol-withdrawal negative emotionality commonly observed during abstinence from chronic alcohol use. METHODS: We subjected C57BL/6 J mice to chronic intermittent ethanol (CIE) exposure schedule to investigate how 72-h withdrawal from alcohol alters affective-like behavior. Next, we determined how treatment with J4, a second-generation adenosine analog, influenced affective behaviors produced by alcohol withdrawal. Finally, we determined how J4 treatment alters voluntary ethanol drinking using the two-bottle-choice drinking paradigm. RESULTS: Our results show that 72-h withdrawal from chronic intermittent ethanol exposure produces limited affective-like disturbances in male C57BL/6 J mice exposed to 4 cycles ethanol vapor. Most importantly, J4 treatment irrespective of ethanol exposure decreases innate anxiety-like behavior in mice. CONCLUSIONS: Withdrawal from chronic intermittent ethanol exposure and subsequent behavioral testing 72 h later produces minimal affective-like behavior. J4 treatment did however reduce marble-burying behavior and increased time spent in open arms of the elevated plus maze, suggesting J4 may be useful as a general anxiolytic.

A PIAS1 Protective Variant S510G Delays polyQ Disease Onset by Modifying Protein Homeostasis.

BACKGROUND: Polyglutamine (polyQ) diseases are dominant neurodegenerative diseases caused by an expansion of the polyQ-encoding CAG repeats in the disease-causing gene. The length of the CAG repeats is the major determiner of the age at onset (AO) of polyQ diseases, including Huntington's disease (HD) and spinocerebellar ataxia type 3 (SCA3). OBJECTIVE: We set out to identify common genetic variant(s) that may affect the AO of polyQ diseases. METHODS: Three hundred thirty-seven patients with HD or SCA3 were enrolled for targeted sequencing of 583 genes implicated in proteinopathies. In total, 16 genes were identified as containing variants that are associated with late AO of polyQ diseases. For validation, we further investigate the variants of PIAS1 because PIAS1 is an E3 SUMO (small ubiquitin-like modifier) ligase for huntingtin (HTT), the protein linked to HD. RESULTS: Biochemical analyses revealed that the ability of PIAS1S510G to interact with mutant huntingtin (mHTT) was less than that of PIAS1WT , resulting in lower SUMOylation of mHTT and lower accumulation of insoluble mHTT. Genetic knock-in of PIAS1S510G in a HD mouse model (R6/2) ameliorated several HD-like deficits (including shortened life spans, poor grip strength and motor coordination) and reduced neuronal accumulation of mHTT. CONCLUSIONS: Our findings suggest that PIAS1 is a genetic modifier of polyQ diseases. The naturally occurring variant, PIAS1S510G , is associated with late AO in polyQ disease patients and milder disease severity in HD mice. Our study highlights the possibility of targeting PIAS1 or pathways governing protein homeostasis as a disease-modifying approach for treating patients with HD. © 2021 International Parkinson and Movement Disorder Society.

A system-wide mislocalization of RNA-binding proteins in motor neurons is a new feature of ALS.

Amyotrophic lateral sclerosis (ALS) is a motor neuron disease characterized by progressive degeneration of motor neurons. Mislocalization of TAR DNA-binding protein 43 (TDP-43) is an early event in the formation of cytoplasmic TDP-43-positive inclusions in motor neurons and a hallmark of ALS. However, the underlying mechanism and the pathogenic impact of this mislocalization are relatively unexplored. We previously reported that abnormal AMPK activation mediates TDP-43 mislocalization in motor neurons of humans and mice with ALS. In the present study, we hypothesized that other nuclear proteins are mislocalized in the cytoplasm of motor neurons due to the AMPK-mediated phosphorylation of importin-α1 and subsequently contribute to neuronal degeneration in ALS. To test this hypothesis, we analyzed motor neurons of sporadic ALS patients and found that when AMPK is activated, importin-α1 is abnormally located in the nucleus. Multiple integrative molecular and cellular approaches (including proteomics, immunoprecipitation/western blot analysis, immunohistological evaluations and gradient analysis of preribosomal complexes) were employed to demonstrate that numerous RNA binding proteins are mislocalized in a rodent motor neuron cell line (NSC34) and human motor neurons derived from iPSCs during AMPK activation. We used comparative proteomic analysis of importin-α1 complexes that were immunoprecipitated with a phosphorylation-deficient mutant of importin-α1 (importin-α1-S105A) and a phosphomimetic mutant of importin-α1 (importin-α1-S105D) to identify 194 proteins that have stronger affinity for the unphosphorylated form than the phosphorylated form of importin-α1. Furthermore, GO and STRING analyses suggested that RNA processing and protein translation is the major machinery affected by abnormalities in the AMPK-importin-α1 axis. Consistently, the expression of importin-α1-S105D alters the assembly of preribosomal complexes and increases cell apoptosis. Collectively, we propose that by impairing importin-α1-mediated nuclear import, abnormal AMPK activation in motor neurons alters the cellular distribution of many RNA-binding proteins, which pathogenically affect multiple cellular machineries in motor neurons and contribute to ALS pathogenesis.

Emerging roles of dysregulated adenosine homeostasis in brain disorders with a specific focus on neurodegenerative diseases.

In modern societies, with an increase in the older population, age-related neurodegenerative diseases have progressively become greater socioeconomic burdens. To date, despite the tremendous effort devoted to understanding neurodegenerative diseases in recent decades, treatment to delay disease progression is largely ineffective and is in urgent demand. The development of new strategies targeting these pathological features is a timely topic. It is important to note that most degenerative diseases are associated with the accumulation of specific misfolded proteins, which is facilitated by several common features of neurodegenerative diseases (including poor energy homeostasis and mitochondrial dysfunction). Adenosine is a purine nucleoside and neuromodulator in the brain. It is also an essential component of energy production pathways, cellular metabolism, and gene regulation in brain cells. The levels of intracellular and extracellular adenosine are thus tightly controlled by a handful of proteins (including adenosine metabolic enzymes and transporters) to maintain proper adenosine homeostasis. Notably, disruption of adenosine homeostasis in the brain under various pathophysiological conditions has been documented. In the past two decades, adenosine receptors (particularly A1 and A2A adenosine receptors) have been actively investigated as important drug targets in major degenerative diseases. Unfortunately, except for an A2A antagonist (istradefylline) administered as an adjuvant treatment with levodopa for Parkinson's disease, no effective drug based on adenosine receptors has been developed for neurodegenerative diseases. In this review, we summarize the emerging findings on proteins involved in the control of adenosine homeostasis in the brain and discuss the challenges and future prospects for the development of new therapeutic treatments for neurodegenerative diseases and their associated disorders based on the understanding of adenosine homeostasis.

Contribution of Energy Dysfunction to Impaired Protein Translation in Neurodegenerative Diseases.

Impaired energy homeostasis and aberrant translational control have independently been implicated in the pathogenesis of neurodegenerative diseases. AMP kinase (AMPK), regulated by the ratio of cellular AMP and ATP, is a major gatekeeper for cellular energy homeostasis. Abnormal regulation of AMPK has been reported in several neurodegenerative diseases, including Alzheimer's disease (AD) and amyotrophic lateral sclerosis (ALS). Most importantly, AMPK activation is known to suppress the translational machinery by inhibiting the mechanistic target of rapamycin complex 1 (mTORC1), activating translational regulators, and phosphorylating nuclear transporter factors. In this review, we describe recent findings on the emerging role of protein translation impairment caused by energy dysregulation in neurodegenerative diseases.

Equilibrative nucleoside transporter 1 inhibition rescues energy dysfunction and pathology in a model of tauopathy.

Tau pathology is instrumental in the gradual loss of neuronal functions and cognitive decline in tauopathies, including Alzheimer's disease (AD). Earlier reports showed that adenosine metabolism is abnormal in the brain of AD patients while consequences remained ill-defined. Herein, we aimed at investigating whether manipulation of adenosine tone would impact Tau pathology, associated molecular alterations and subsequent neurodegeneration. We demonstrated that treatment with an inhibitor (J4) of equilibrative nucleoside transporter 1 (ENT1) exerted beneficial effects in a mouse model of Tauopathy. Treatment with J4 not only reduced Tau hyperphosphorylation but also rescued memory deficits, mitochondrial dysfunction, synaptic loss, and abnormal expression of immune-related gene signatures. These beneficial effects were particularly ascribed to the ability of J4 to suppress the overactivation of AMPK (an energy reduction sensor), suggesting that normalization of energy dysfunction mitigates neuronal dysfunctions in Tauopathy. Collectively, these data highlight that targeting adenosine metabolism is a novel strategy for tauopathies.