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Huntington's disease (HD) is caused by a CAG repeat expansion in exon1 of the HTT gene that encodes a polyglutamine tract in huntingtin protein. The formation of HTT exon1 fragments with an expanded polyglutamine repeat has been implicated as a key step in the pathogenesis of HD. It was reported that the CAG repeat length-dependent aberrant splicing of exon1 HTT results in a short polyadenylated mRNA that is translated into an exon1 HTT protein. Under normal conditions, TDP-43 is predominantly found in the nucleus, where it regulates gene expression. However, in various pathological conditions, TDP-43 is mislocalized in the cytoplasm. By investigating HD knock-in mice, we explore whether the pathogenic TDP-43 in the cytoplasm contributes to HD pathogenesis, through expressing the cytoplasmic TDP-43 without nuclear localization signal. We found that the cytoplasmic TDP-43 is increased in the HD mouse brain and that its mislocalization could deteriorate the motor and gait behavior. Importantly, the cytoplasmic TDP-43, via its binding to the intron1 sequence (GU/UG)n of the mouse Htt pre-mRNA, promotes the transport of exon1-intron1 Htt onto ribosome, resulting in the aberrant generation of exon1 Htt. Our findings suggest that cytoplasmic TDP-43 contributes to HD pathogenesis via its binding to and transport of nuclear un-spliced mRNA to the ribosome for the generation of a toxic protein product.
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INTRODUCTION: Aging is one of the risk factors for the early onset of Alzheimer's disease (AD). We previously discovered that the age-dependent increase in Ubiquitin Conjugating Enzyme E2 N (UBE2N) plays a role in the accumulation of misfolded proteins through K63 ubiquitination, which has been linked to AD pathogenesis. However, the impact of UBE2N on amyloid pathology and clearance has remained unknown. RESULTS: We observed the elevated UBE2N during the amyloid beta (Aß) generation in the brains of 5×FAD, APP/PS1 mice, and patients with AD, in comparison to healthy individuals. UBE2N overexpression exacerbated amyloid deposition in 5×FAD mice and senescent monkeys, whereas knocking down UBE2N via CRISPR/Cas9 reduced Aß generation and cognitive deficiency. Moreover, pharmacological inhibition of UBE2N ameliorated Aß pathology and subsequent transcript defects in 5×FAD mice. DISCUSSION: We have discovered that age-dependent expression of UBE2N is a critical regulator of AD pathology. Our findings suggest that UBE2N could serve as a potential pharmacological target for the advancement of AD therapeutics. HIGHLIGHTS: Ubiquitin Conjugating Enzyme E2 N (UBE2N) level was elevated during amyloid beta (Aß) deposition in AD mouse and patients' brains. UBE2N exacerbated Aß generation in the AD mouse and senescent monkey. Drug inhibition of UBE2N ameliorated Aß pathology and cognitive deficiency.
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ABSTRACT: Spinal and bulbar muscular atrophy (SBMA) is a neurodegenerative disease caused by extended CAG trinucleotide repeats in the androgen receptor (AR) gene, which encodes a ligand-dependent transcription factor. The mutant AR protein, characterized by polyglutamine expansion, is prone to misfolding and forms aggregates in both the nucleus and cytoplasm in the brain in SBMA patients. These aggregates alter protein-protein interactions and compromise transcriptional activity. In this study, we reported that in both cultured N2a cells and mouse brain, mutant AR with polyglutamine expansion causes reduced expression of mesencephalic astrocyte-derived neurotrophic factor (MANF). Overexpression of MANF ameliorated the neurotoxicity of mutant AR through the inhibition of mutant AR aggregation. Conversely, knocking down endogenous MANF in the mouse brain exacerbated neuronal damage and mutant AR aggregation. Our findings suggest that inhibition of MANF expression by mutant AR is a potential mechanism underlying neurodegeneration in SBMA.
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Growing evidence indicates that non-neuronal oligodendrocyte plays an important role in Amyotrophic lateral sclerosis (ALS) and other neurodegenerative diseases. In patient's brain, the impaired myelin structure is a pathological feature with the observation of TDP-43 in cytoplasm of oligodendrocyte. However, the mechanism underlying the gain of function by TDP-43 in oligodendrocytes, which are vital for the axonal integrity, remains unclear. Recently, we found that the primate-specific cleavage of truncated TDP-43 fragments occurred in cytoplasm of monkey neural cells. This finding opened up the avenue to investigate the myelin integrity affected by pathogenic TDP-43 in oligodendrocytes. In current study, we demonstrated that the truncated TDP-35 in oligodendrocytes specifically, could lead to the dysfunctional demyelination in corpus callosum of monkey. As a consequence of the interaction of myelin regulatory factor with the accumulated TDP-35 in cytoplasm, the downstream myelin-associated genes expression was downregulated at the transcriptional level. Our study aims to investigate the potential effect on myelin structure injury, affected by the truncated TDP-43 in oligodendrocyte, which provided the additional clues on the gain of function during the progressive pathogenesis and symptoms in TDP-43 related diseases.
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Huntington's disease (HD) is an autosomal dominant neurodegenerative disease characterized by preferential neuronal loss in the striatum. The mechanism underlying striatal selective neurodegeneration remains unclear, making it difficult to develop effective treatments for HD. In the brains of nonhuman primates, we examined the expression of Huntingtin (HTT), the gene responsible for HD. We found that HTT protein is highly expressed in striatal neurons due to its slow degradation in the striatum. We also identified tripartite motif-containing 37 (TRIM37) as a primate-specific protein that interacts with HTT and is selectively reduced in the primate striatum. TRIM37 promotes the ubiquitination and degradation of mutant HTT (mHTT) in vitro and modulates mHTT aggregation in mouse and monkey brains. Our findings suggest that nonhuman primates are crucial for understanding the mechanisms of human diseases such as HD and support TRIM37 as a potential therapeutic target for treating HD.
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Corpo Estriado , Proteína Huntingtina , Doença de Huntington , Proteínas com Motivo Tripartido , Ubiquitina-Proteína Ligases , Ubiquitinação , Animais , Humanos , Camundongos , Corpo Estriado/metabolismo , Corpo Estriado/patologia , Modelos Animais de Doenças , Proteína Huntingtina/genética , Proteína Huntingtina/metabolismo , Doença de Huntington/metabolismo , Doença de Huntington/patologia , Doença de Huntington/genética , Neurônios/metabolismo , Neurônios/patologia , Primatas , Proteólise , Proteínas com Motivo Tripartido/metabolismo , Proteínas com Motivo Tripartido/genética , Ubiquitina-Proteína Ligases/metabolismo , Ubiquitina-Proteína Ligases/genética , Macaca fascicularisRESUMO
Huntington's disease (HD) is a monogenic neurodegenerative disease, caused by the CAG trinucleotide repeat expansion in exon 1 of the Huntingtin (HTT) gene. The HTT gene encodes a large protein known to interact with many proteins. Huntingtin-associated protein 40 (HAP40) is one that shows high binding affinity with HTT and functions to maintain HTT conformation in vitro. However, the potential role of HAP40 in HD pathogenesis remains unknown. In this study, we found that the expression level of HAP40 is in parallel with HTT but inversely correlates with mutant HTT aggregates in mouse brains. Depletion of endogenous HAP40 in the striatum of HD140Q knock-in (KI) mice leads to enhanced mutant HTT aggregation and neuronal loss. Consistently, overexpression of HAP40 in the striatum of HD140Q KI mice reduced mutant HTT aggregation and ameliorated the behavioral deficits. Mechanistically, HAP40 preferentially binds to mutant HTT and promotes Lysine 48-linked ubiquitination of mutant HTT. Our results revealed that HAP40 is an important regulator of HTT protein homeostasis in vivo and hinted at HAP40 as a therapeutic target in HD treatment.
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Proteína Huntingtina , Doença de Huntington , Animais , Humanos , Camundongos , Corpo Estriado/metabolismo , Corpo Estriado/patologia , Modelos Animais de Doenças , Proteína Huntingtina/metabolismo , Proteína Huntingtina/genética , Doença de Huntington/metabolismo , Doença de Huntington/genética , Doença de Huntington/patologia , Camundongos Transgênicos , Mutação , Neurônios/metabolismo , Neurônios/patologia , Agregados Proteicos , Agregação Patológica de Proteínas/genética , Agregação Patológica de Proteínas/metabolismo , Ubiquitinação , Peptídeos e Proteínas de Sinalização Intracelular/metabolismoRESUMO
Huntington's disease (HD) arises from the abnormal expansion of CAG repeats in the huntingtin gene (HTT), resulting in the production of the mutant huntingtin protein (mHTT) with a polyglutamine stretch in its N-terminus. The pathogenic mechanisms underlying HD are complex and not yet fully elucidated. However, mHTT forms aggregates and accumulates abnormally in neuronal nuclei and processes, leading to disruptions in multiple cellular functions. Although there is currently no effective curative treatment for HD, significant progress has been made in developing various therapeutic strategies to treat HD. In addition to drugs targeting the neuronal toxicity of mHTT, gene therapy approaches that aim to reduce the expression of the mutant HTT gene hold great promise for effective HD therapy. This review provides an overview of current HD treatments, discusses different therapeutic strategies, and aims to facilitate future therapeutic advancements in the field.
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Doença de Huntington , Humanos , Doença de Huntington/genética , Doença de Huntington/terapia , Terapia Genética , Proteínas MutantesRESUMO
Huntington's disease (HD) is a hereditary neurodegenerative disorder for which there is currently no effective treatment available. Consequently, the development of appropriate disease models is critical to thoroughly investigate disease progression. The genetic basis of HD involves the abnormal expansion of CAG repeats in the huntingtin ( HTT) gene, leading to the expansion of a polyglutamine repeat in the HTT protein. Mutant HTT carrying the expanded polyglutamine repeat undergoes misfolding and forms aggregates in the brain, which precipitate selective neuronal loss in specific brain regions. Animal models play an important role in elucidating the pathogenesis of neurodegenerative disorders such as HD and in identifying potential therapeutic targets. Due to the marked species differences between rodents and larger animals, substantial efforts have been directed toward establishing large animal models for HD research. These models are pivotal for advancing the discovery of novel therapeutic targets, enhancing effective drug delivery methods, and improving treatment outcomes. We have explored the advantages of utilizing large animal models, particularly pigs, in previous reviews. Since then, however, significant progress has been made in developing more sophisticated animal models that faithfully replicate the typical pathology of HD. In the current review, we provide a comprehensive overview of large animal models of HD, incorporating recent findings regarding the establishment of HD knock-in (KI) pigs and their genetic therapy. We also explore the utilization of large animal models in HD research, with a focus on sheep, non-human primates (NHPs), and pigs. Our objective is to provide valuable insights into the application of these large animal models for the investigation and treatment of neurodegenerative disorders.
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Doença de Huntington , Doenças dos Ovinos , Doenças dos Suínos , Animais , Ovinos , Suínos , Doença de Huntington/genética , Doença de Huntington/terapia , Doença de Huntington/metabolismo , Doença de Huntington/veterinária , Modelos Animais de Doenças , Primatas/genética , Encéfalo/metabolismo , Proteína Huntingtina/genética , Proteína Huntingtina/metabolismo , Doenças dos Ovinos/metabolismo , Doenças dos Ovinos/patologia , Doenças dos Suínos/metabolismo , Doenças dos Suínos/patologiaRESUMO
PTEN-induced putative kinase 1 (PINK1), a mitochondrial kinase that phosphorylates Parkin and other proteins, plays a crucial role in mitophagy and protection against neurodegeneration. Mutations in PINK1 and Parkin can lead to loss of function and early onset Parkinson's disease. However, there is a lack of strong in vivo evidence in rodent models to support the theory that loss of PINK1 affects mitophagy and induces neurodegeneration. Additionally, PINK1 knockout pigs ( Sus scrofa) do not appear to exhibit neurodegeneration. In our recent work involving non-human primates, we found that PINK1 is selectively expressed in primate brains, while absent in rodent brains. To extend this to other species, we used multiple antibodies to examine the expression of PINK1 in pig tissues. In contrast to tissues from cynomolgus monkeys ( Macaca fascicularis), our data did not convincingly demonstrate detectable PINK1 expression in pig tissues. Knockdown of PINK1 in cultured pig cells did not result in altered Parkin and BAD phosphorylation, as observed in cultured monkey cells. A comparison of monkey and pig striatum revealed more PINK1-phosphorylated substrates in the monkey brain. Consistently, PINK1 knockout in pigs did not lead to obvious changes in the phosphorylation of Parkin and BAD. These findings provide new evidence that PINK1 expression is specific to primates, underscoring the importance of non-human primates in investigating PINK1 function and pathology related to PINK1 deficiency.
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Primatas , Proteínas Quinases , Animais , Fosforilação , Proteínas Quinases/genética , Proteínas Quinases/metabolismo , Primatas/genética , Ubiquitina-Proteína Ligases/genética , Ubiquitina-Proteína Ligases/metabolismo , HaplorrinosRESUMO
Neurodegenerative diseases (NDs) are a group of debilitating neurological disorders that primarily affect elderly populations and include Alzheimer's disease (AD), Parkinson's disease (PD), Huntington's disease (HD), and amyotrophic lateral sclerosis (ALS). Currently, there are no therapies available that can delay, stop, or reverse the pathological progression of NDs in clinical settings. As the population ages, NDs are imposing a huge burden on public health systems and affected families. Animal models are important tools for preclinical investigations to understand disease pathogenesis and test potential treatments. While numerous rodent models of NDs have been developed to enhance our understanding of disease mechanisms, the limited success of translating findings from animal models to clinical practice suggests that there is still a need to bridge this translation gap. Old World non-human primates (NHPs), such as rhesus, cynomolgus, and vervet monkeys, are phylogenetically, physiologically, biochemically, and behaviorally most relevant to humans. This is particularly evident in the similarity of the structure and function of their central nervous systems, rendering such species uniquely valuable for neuroscience research. Recently, the development of several genetically modified NHP models of NDs has successfully recapitulated key pathologies and revealed novel mechanisms. This review focuses on the efficacy of NHPs in modeling NDs and the novel pathological insights gained, as well as the challenges associated with the generation of such models and the complexities involved in their subsequent analysis.
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Doenças Neurodegenerativas , Doença de Parkinson , Humanos , Animais , Chlorocebus aethiops , Doenças Neurodegenerativas/genética , Doenças Neurodegenerativas/terapia , Doenças Neurodegenerativas/veterinária , Animais Geneticamente Modificados , Modelos Animais de Doenças , Doença de Parkinson/patologia , Doença de Parkinson/veterinária , Macaca mulattaRESUMO
Schizophrenia is a highly heritable neuropsychiatric disorder characterized by cognitive and social dysfunction. Genetic, epigenetic, and environmental factors are together implicated in the pathogenesis and development of schizophrenia. DNA methylation, 5-methycytosine (5mC) and 5-hydroxylcytosine (5hmC) have been recognized as key epigenetic elements in neurodevelopment, ageing, and neurodegenerative diseases. Recently, distinctive 5mC and 5hmC pattern and expression changes of related genes have been discovered in schizophrenia. Antipsychotic drugs that affect 5mC status can alleviate symptoms in patients with schizophrenia, suggesting a critical role for DNA methylation in the pathogenesis of schizophrenia. Further exploring the signatures of 5mC and 5hmC in schizophrenia and developing precision-targeted epigenetic drugs based on this will provide new insights into the diagnosis and treatment of schizophrenia.
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Antipsicóticos , Esquizofrenia , Humanos , 5-Metilcitosina , Esquizofrenia/genética , EnvelhecimentoRESUMO
The nuclear loss and cytoplasmic accumulation of TDP-43 (TAR DNA/RNA binding protein 43) are pathological hallmarks of amyotrophic lateral sclerosis (ALS) and frontotemporal lobar degeneration (FTLD). Previously, we reported that the primate-specific cleavage of TDP-43 accounts for its cytoplasmic mislocalization in patients' brains. This prompted us to investigate further whether and how the loss of nuclear TDP-43 mediates neuropathology in primate brain. In this study, we report that TDP-43 knockdown at the similar effectiveness, induces more damage to neuronal cells in the monkey brain than rodent mouse. Importantly, the loss of TDP-43 suppresses the E3 ubiquitin ligase PJA1 expression in the monkey brain at transcriptional level, but yields an opposite upregulation of PJA1 in the mouse brain. This distinct effect is due to the species-dependent binding of nuclear TDP-43 to the unique promoter sequences of the PJA1 genes. Further analyses reveal that the reduction of PJA1 accelerates neurotoxicity, whereas overexpressing PJA1 diminishes neuronal cell death by the TDP-43 knockdown in vivo. Our findings not only uncover a novel primate-specific neurotoxic contribution to the loss of function theory of TDP-43 proteinopathy, but also underscore a potential therapeutic approach of PJA1 to the loss of nuclear TDP-43.
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Esclerose Lateral Amiotrófica , Encéfalo , Proteínas de Ligação a DNA , Ubiquitina-Proteína Ligases , Animais , Esclerose Lateral Amiotrófica/genética , Proteínas de Ligação a DNA/genética , Haplorrinos , Transcrição Gênica , Ubiquitina-Proteína Ligases/genética , Modelos Animais de DoençasRESUMO
Our previous work has established a knockin (KI) pig model of Huntington's disease (HD) that can replicate the typical pathological features of HD, including selective striatal neuronal loss, reactive gliosis, and axonal degeneration. However, HD KI mice exhibit milder neuropathological phenotypes and lack overt neurodegeneration. By performing RNA sequencing to compare the gene expression profiles between HD KI pigs and mice, we find that genes related to interleukin-17 (IL-17) signaling are upregulated in the HD pig brains compared to the mouse brains. Delivery of IL-17 into the brain striatum of HD KI mice causes greater reactive gliosis and synaptic deficiency compared to HD KI mice that received PBS. These findings suggest that the upregulation of genes related to IL-17 signaling in HD pig brains contributes to severe glial pathology in HD and identify this as a potential therapeutic target for treating HD.
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Doença de Huntington , Animais , Camundongos , Corpo Estriado/metabolismo , Modelos Animais de Doenças , Gliose/patologia , Doença de Huntington/metabolismo , Interleucina-17/genética , Interleucina-17/metabolismo , Camundongos Transgênicos , Neurônios/metabolismo , SuínosRESUMO
Accumulation of misfolded proteins leads to many neurodegenerative diseases that can be treated by lowering or removing mutant proteins. Huntington's disease (HD) is characterized by the intracellular accumulation of mutant huntingtin (mHTT) that can be soluble and aggregated in the central nervous system and causes neuronal damage and death. Here, an intracellular antibody (intrabody) fragment is generated that can specifically bind mHTT and link to the lysosome for degradation. It is found that delivery of this peptide by either brain injection or intravenous administration can efficiently clear the soluble and aggregated mHTT by activating the lysosomal degradation pathway, resulting in amelioration of gliosis and dyskinesia in HD knock-in (KI-140Q) mice. These findings suggest that the small intrabody peptide linked to lysosomes can effectively lower mutant proteins and provide a new approach for treating neurodegenerative diseases that are caused by the accumulation of mutant proteins.
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Doença de Huntington , Doenças Neurodegenerativas , Animais , Camundongos , Proteína Huntingtina/genética , Proteína Huntingtina/metabolismo , Doença de Huntington/metabolismo , Lisossomos/metabolismo , Proteínas Mutantes , Proteínas do Tecido Nervoso , PeptídeosRESUMO
In order to dissect amyotrophic lateral sclerosis (ALS), a multigenic, multifactorial, and progressive neurodegenerative disease with heterogeneous clinical presentations, researchers have generated numerous animal models to mimic the genetic defects. Concurrent and comparative analysis of these various models allows identification of the causes and mechanisms of ALS in order to finally obtain effective therapeutics. However, most genetically modified rodent models lack overt pathological features, imposing challenges and limitations in utilizing them to rigorously test the potential mechanisms. Recent studies using large animals, including pigs and non-human primates, have uncovered important events that resemble neurodegeneration in patients' brains but could not be produced in small animals. Here we describe common features as well as discrepancies among these models, highlighting new insights from these models. Furthermore, we will discuss how to make rodent models more capable of recapitulating important pathological features based on the important pathogenic insights from large animal models.
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Esclerose Lateral Amiotrófica , Doenças Neurodegenerativas , Humanos , Animais , Suínos , Esclerose Lateral Amiotrófica/genética , EncéfaloRESUMO
Tauopathy, characterized by the hyperphosphorylation and accumulation of the microtubule-associated protein tau, and the accumulation of Aß oligomers, constitute the major pathological hallmarks of Alzheimer's disease. However, the relationship and causal roles of these two pathological changes in neurodegeneration remain to be defined, even though they occur together or independently in several neurodegenerative diseases associated with cognitive and movement impairment. While it is widely accepted that Aß accumulation leads to tauopathy in the late stages of the disease, it is still unknown whether tauopathy influences the formation of toxic Aß oligomers. To address this, we generated transgenic cynomolgus monkey models expressing Tau (P301L) through lentiviral infection of monkey embryos. These monkeys developed age-dependent neurodegeneration and motor dysfunction. Additionally, we performed a stereotaxic injection of adult monkey and mouse brains to express Tau (P301L) via AAV9 infection. Importantly, we found that tauopathy resulting from embryonic transgenic Tau expression or stereotaxic brain injection of AAV-Tau selectively promoted the generation of Aß oligomers in the monkey spinal cord. These Aß oligomers were recognized by several antibodies to Aß1-42 and contributed to neurodegeneration. However, the generation of Aß oligomers was not observed in other brain regions of Tau transgenic monkeys or in the brains of mice injected with AAV9-Tau (P301L), suggesting that the generation of Aß oligomers is species- and brain region-dependent. Our findings demonstrate for the first time that tauopathy can trigger Aß pathology in the primate spinal cord and provide new insight into the pathogenesis and treatment of tauopathy.
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Doença de Alzheimer , Tauopatias , Animais , Camundongos , Macaca fascicularis , Tauopatias/genética , Peptídeos beta-Amiloides/genética , Doença de Alzheimer/genética , Medula EspinalRESUMO
Huntington's disease (HD) is an autosomal-dominant inherited neurodegenerative disease caused by a CAG repeat expansion in exon1 of the huntingtin gene (HTT). This expansion leads to the production of N-terminal mutant huntingtin protein (mHtt) that contains an expanded polyglutamine tract, which is toxic to neurons and causes neurodegeneration. While the production of N-terminal mHtt can be mediated by proteolytic cleavage of full-length mHtt, abnormal splicing of exon1-intron1 of mHtt has also been identified in the brains of HD mice and patients. However, the proportion of aberrantly spliced exon1 mHTT in relation to normal mHTT exon remains to be defined. In this study, HTT exon1 production was examined in the HD knock-in (KI) pig model, which more closely recapitulates neuropathology seen in HD patient brains than HD mouse models. The study revealed that aberrant spliced HTT exon1 is also present in the brains of HD pigs, but it is expressed at a much lower level than the normally spliced HTT exon products. These findings suggest that careful consideration is needed when assessing the contribution of aberrantly spliced mHTT exon1 to HD pathogenesis, and further rigorous investigation is required.
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Huntington's disease (HD) is caused by an expansion of a CAG repeat in the gene that encodes the huntingtin protein (HTT). The exact function of HTT is still not fully understood, and previous studies have mainly focused on identifying proteins that interact with HTT to gain insights into its function. Numerous HTT-interacting proteins have been discovered, shedding light on the functions and structure of HTT. Most of these proteins interact with the N-terminal region of HTT. Among the various HTT-interacting proteins, huntingtin-associated protein 1 (HAP1) and HTT-interacting protein 1 (HIP1) have been extensively studied. Recent research has uncovered differences in the distribution of HAP1 in monkey and human brains compared with mice. This finding suggests that there may be species-specific variations in the regulation and function of HTT-interacting proteins. Understanding these differences could provide crucial insights into the development of HD. In this review, we will focus on the recent advancements in the study of HTT-interacting proteins, with particular attention to the differential distributions of HTT and HAP1 in larger animal models.
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Encéfalo , Doença de Huntington , Humanos , Animais , Camundongos , Proteína Huntingtina/genética , Doença de Huntington/genética , Modelos Animais , Especificidade da EspécieRESUMO
Epigenetic methylation has been shown to play an important role in transcriptional regulation and disease pathogenesis. Recent advancements in detection techniques have identified DNA N6-methyldeoxyadenosine (6mA) and RNA N6-methyladenosine (m6A) as methylation modifications at the sixth position of adenine in DNA and RNA, respectively. While the distributions and functions of 6mA and m6A have been extensively studied in prokaryotes, their roles in the mammalian brain, where they are enriched, are still not fully understood. In this review, we provide a comprehensive summary of the current research progress on 6mA and m6A, as well as their associated writers, erasers, and readers at both DNA and RNA levels. Specifically, we focus on the potential roles of 6mA and m6A in the fundamental biological pathways of the mammalian genome and highlight the significant regulatory functions of 6mA in neurodegenerative diseases.