α-Synuclein reduces acetylserotonin O-methyltransferase mediated melatonin biosynthesis by microtubule-associated protein 1 light chain 3 beta-related degradation pathway.

Previous studies have demonstrated that α-synuclein (α-SYN) is closely associated with rapid eye movement sleep behavior disorder (RBD) related to several neurodegenerative disorders. However, the exact molecular mechanisms are still rarely investigated. In the present study, we found that in the α-SYNA53T induced RBD-like behavior mouse model, the melatonin level in the plasma and pineal gland were significantly decreased. To elucidate the underlying mechanism of α-SYN-induced melatonin reduction, we investigated the effect of α-SYN in melatonin biosynthesis. Our findings showed that α-SYN reduced the level and activity of melatonin synthesis enzyme acetylserotonin O-methyltransferase (ASMT) in the pineal gland and in the cell cultures. In addition, we found that microtubule-associated protein 1 light chain 3 beta (LC3B) as an important autophagy adapter is involved in the degradation of ASMT. Immunoprecipitation assays revealed that α-SYN increases the binding between LC3B and ASMT, leading to ASMT degradation and a consequent reduction in melatonin biosynthesis. Collectively, our results demonstrate the molecular mechanisms of α-SYN in melatonin biosynthesis, indicating that melatonin is an important molecule involved in the α-SYN-associated RBD-like behaviors, which may provide a potential therapeutic target for RBD of Parkinson's disease.

CircRNA and Stroke: New Insight of Potential Biomarkers and Therapeutic Targets.

Stroke, the second-largest cause of death and the leading cause of disability globally, presents significant challenges in terms of prognosis and treatment. Identifying reliable prognosis biomarkers and treatment targets is crucial to address these challenges. Circular RNA (circRNA) has emerged as a promising research biomarkers and therapeutic targets because of its tissue specificity and conservation. However, the potential role of circRNA in stroke prognosis and treatment remains largely unexplored. This review briefly elucidate the mechanism underlying circRNA's involvement in stroke pathophysiology. Additionally, this review summarizes the impact of circRNA on different forms of strokes, including ischemic stroke and hemorrhagic stroke. And, this article discusses the positive effects of circRNA on promoting cerebrovascular repair and regeneration, maintaining the integrity of the blood-brain barrier (BBB), and reducing neuronal injury and immune inflammatory response. In conclusion, the significance of circRNA as a potential prognostic biomarker and a viable therapeutic target was underscored.

Integrative analysis of metabolomics and proteomics unravels purine metabolism dysregulation in the SOD1G93A mouse model of amyotrophic lateral sclerosis.

Amyotrophic lateral sclerosis (ALS) is a fatal neurodegenerative disease with progressive paralysis of limbs and bulb in patients, the cause of which remains unclear. Accumulating studies suggest that motor neuron degeneration is associated with systemic metabolic impairment in ALS. However, the metabolic reprogramming and underlying mechanism in the longitudinal progression of the disease remain poorly understood. In this study, we aimed to investigate the molecular changes at both metabolic and proteomic levels during disease progression to identify the most critical metabolic pathways and underlying mechanisms involved in ALS pathophysiological changes. Utilizing liquid chromatography-mass spectrometry-based metabolomics, we analyzed the metabolites' levels of plasma, lumbar spinal cord, and motor cortex from SOD1G93A mice and wildtype (WT) littermates at different stages. To elucidate the regulatory network underlying metabolic changes, we further analyzed the proteomics profile in the spinal cords of SOD1G93A and WT mice. A group of metabolites implicated in purine metabolism, methionine cycle, and glycolysis were found differentially expressed in ALS mice, and abnormal expressions of enzymes involved in these metabolic pathways were also confirmed. Notably, we first demonstrated that dysregulation of purine metabolism might contribute to the pathogenesis and disease progression of ALS. Furthermore, we discovered that fatty acid metabolism, TCA cycle, arginine and proline metabolism, and folate-mediated one­carbon metabolism were also significantly altered in this disease. The identified differential metabolites and proteins in our study could complement existing data on metabolic reprogramming in ALS, which might provide new insight into the pathological mechanisms and novel therapeutic targets of ALS.

The role of Nurr1-miR-30e-5p-NLRP3 axis in inflammation-mediated neurodegeneration: insights from mouse models and patients' studies in Parkinson's disease.

Nuclear receptor related-1 (Nurr1), a ligand-activated transcription factor, is considered a potential susceptibility gene for Parkinson's disease (PD), and has been demonstrated to possess protective effects against inflammation-induced neuronal damage. Despite the evidence showing decreased NURR1 level and increased pro-inflammatory cytokines in cell and animal models as well as in PD patients' peripheral blood mononuclear cells (PBMCs), the underlying mechanism remains elusive. In this study, we investigated the molecular mechanism of Nurr1 in PD-related inflammation. Through the miRNA-sequencing and verification in PBMCs from a cohort of 450 individuals, we identified a significant change of a Nurr1-dependent miRNA miR-30e-5p in PD patients compared to healthy controls (HC). Additionally, PD patients exhibited an elevated plasma interleukin-1ß (IL-1ß) level and increased nucleotide-binding domain-like receptor protein 3 (NLRP3) expression in PBMCs compared to HC. Statistical analyses revealed significant correlations among NURR1, miR-30e-5p, and NLRP3 levels in the PBMCs of PD patients. To further explore the involvement of Nurr1-miR-30e-5p-NLRP3 axis in the inflammation-mediated PD pathology, we developed a mouse model (Nurr1flox+/Cd11b-cre+, Nurr1cKO) conditionally knocking out Nurr1 in Cd11b-expressing cells. Our investigations in Nurr1cKO mice unveiled significant dopaminergic neurodegeneration following lipopolysaccharide-induced inflammation. Remarkably, Nurr1 deficiency triggered microglial activation and activated NLRP3 inflammasome, resulting in increased IL-1ß secretion. Coincidently, we found that miR-30e-5p level was significantly decreased in the PBMCs and primary microglia of Nurr1cKO mice compared to the controls. Furthermore, our in vitro experiments demonstrated that miR-30e-5p specifically targeted NLRP3. In Nurr1-knockdown microglia, NLRP3 expression was upregulated via miR-30e-5p. In summary, our findings highlight the involvement of Nurr1-miR-30e-5p-NLRP3 axis in the inflammation-mediated neurodegeneration in PD, the results of which may offer promising prospects for developing PD biomarkers and targeted therapeutic interventions.

Cell-therapy for Parkinson's disease: a systematic review and meta-analysis.

BACKGROUND: Cell-based strategies focusing on replacement or protection of dopaminergic neurons have been considered as a potential approach to treat Parkinson's disease (PD) for decades. However, despite promising preclinical results, clinical trials on cell-therapy for PD reported mixed outcomes and a thorough synthesis of these findings is lacking. We performed a systematic review and meta-analysis to evaluate cell-therapy for PD patients. METHODS: We systematically identified all clinical trials investigating cell- or tissue-based therapies for PD published before July 2023. Out of those, studies reporting transplantation of homogenous cells (containing one cell type) were included in meta-analysis. The mean difference or standardized mean difference in quantitative neurological scale scores before and after cell-therapy was analyzed to evaluate treatment effects. RESULTS: The systematic literature search revealed 106 articles. Eleven studies reporting data from 11 independent trials (210 patients) were eligible for meta-analysis. Disease severity and motor function evaluation indicated beneficial effects of homogenous cell-therapy in the 'off' state at 3-, 6-, 12-, or 24-month follow-ups, and for motor function even after 36 months. Most of the patients were levodopa responders (61.6-100% in different follow-ups). Cell-therapy was also effective in improving the daily living activities in the 'off' state of PD patients. Cells from diverse sources were used and multiple transplantation modes were applied. Autografts did not improve functional outcomes, while allografts exhibited beneficial effects. Encouragingly, both transplantation into basal ganglia and to areas outside the basal ganglia were effective to reduce disease severity. Some trials reported adverse events potentially related to the surgical procedure. One confirmed and four possible cases of graft-induced dyskinesia were reported in two trials included in this meta-analysis. CONCLUSIONS: This meta-analysis provides preliminary evidence for the beneficial effects of homogenous cell-therapy for PD, potentially to the levodopa responders. Allogeneic cells were superior to autologous cells, and the effective transplantation sites are not limited to the basal ganglia. PROSPERO registration number: CRD42022369760.

Mettl14-mediated m6A modification is essential for visual function and retinal photoreceptor survival.

BACKGROUND: As the most abundant epigenetic modification of eukaryotic mRNA, N6-methyladenosine (m6A) modification has been shown to play a role in mammalian nervous system development and function by regulating mRNA synthesis and degeneration. However, the role of m6A modification in retinal photoreceptors remains unknown. RESULTS: We generated the first retina-specific Mettl14-knockout mouse models using the Rho-Cre and HRGP-Cre lines and investigated the functions of Mettl14 in retinal rod and cone photoreceptors. Our data showed that loss of Mettl14 in rod cells causes a weakened scotopic photoresponse and rod degeneration. Further study revealed the ectopic accumulation of multiple outer segment (OS) proteins in the inner segment (IS). Deficiency of Mettl14 in cone cells led to the mislocalization of cone opsin proteins and the progressive death of cone cells. Moreover, Mettl14 depletion resulted in drastic decreases in METTL3/WTAP levels and reduced m6A methylation levels. Mechanistically, transcriptomic analyses in combination with MeRIP-seq illustrated that m6A depletion via inactivation of Mettl14 resulted in reduced expression levels of multiple phototransduction- and cilium-associated genes, which subsequently led to compromised ciliogenesis and impaired synthesis and transport of OS-residing proteins in rod cells. CONCLUSIONS: Our data demonstrate that Mettl14 plays an important role in regulating phototransduction and ciliogenesis events and is essential for photoreceptor function and survival, highlighting the importance of m6A modification in visual function.

The electrophysiological and neuropathological profiles of cerebellum in APPswe /PS1ΔE9 mice: A hypothesis on the role of cerebellum in Alzheimer's disease.

We propose the hypothesis that the cerebellar electrophysiology and sleep-wake cycles may be altered at the early stage of Alzheimer's disease (AD), proceeding the amyloid-ß neuropathological hallmarks. The electrophysiologic characteristics of cerebellum thereby might be served as a biomarker in the prepathological detection of AD. Sleep disturbances are common in preclinical AD patients, and the cerebellum has been implicated in sleep-wake regulation by several pioneer studies. Additionally, recent studies suggest that the structure and function of the cerebellum may be altered at the early stages of AD, indicating that the cerebellum may be involved in the disease's progression. We used APPswe /PS1ΔE9 mice as a model of AD, monitored and analyzed electroencephalogram data, and assessed neuropathological profiles in the cerebellum of AD mice. Our hypothesis may establish a linkage between the cerebellum and AD, thereby potentially providing new perspectives on the pathogenesis of the disease.

The Crucial Roles of Pitx3 in Midbrain Dopaminergic Neuron Development and Parkinson's Disease-Associated Neurodegeneration.

The degeneration of midbrain dopaminergic (mDA) neurons, particularly in the substantia nigra pars compacta (SNc), is one of the most prominent pathological hallmarks of Parkinson's disease (PD). To uncover the pathogenic mechanisms of mDA neuronal death during PD may provide therapeutic targets to prevent mDA neuronal loss and slow down the disease's progression. Paired-like homeodomain transcription factor 3 (Pitx3) is selectively expressed in the mDA neurons as early as embryonic day 11.5 and plays a critical role in mDA neuron terminal differentiation and subset specification. Moreover, Pitx3-deficient mice exhibit some canonical PD-related features, including the profound loss of SNc mDA neurons, a dramatic decrease in striatal dopamine (DA) levels, and motor abnormalities. However, the precise role of Pitx3 in progressive PD and how this gene contributes to mDA neuronal specification during early stages remains unclear. In this review, we updated the latest findings on Pitx3 by summarizing the crosstalk between Pitx3 and its associated transcription factors in mDA neuron development. We further explored the potential benefits of Pitx3 as a therapeutic target for PD in the future. To better understand the transcriptional network of Pitx3 in mDA neuron development may provide insights into Pitx3-related clinical drug-targeting research and therapeutic approaches.

Recent research advances of the biomimetic tumor microenvironment and regulatory factors on microfluidic devices: A systematic review.

Tumor microenvironment is a multicomponent system consisting of tumor cells, noncancer cells, extracellular matrix, and signaling molecules, which hosts tumor cells with integrated biophysical and biochemical elements. Because of its critical involvement in tumor genesis, invasion, metastasis, and resistance, the tumor microenvironment is emerging as a hot topic of tumor biology and a prospective therapeutic target. Unfortunately, the complex of microenvironment modeling in vitro is technically challenging and does not effectively generalize the local tumor tissue milieu. Recently, significant advances in microfluidic technologies have provided us with an approach to imitate physiological systems that can be utilized to mimic the characterization of tumor responses with pathophysiological relevance in vitro. In this review, we highlight the recent progress and innovations in microfluidic technology that facilitates the tumor microenvironment study. We also discuss the progress and future perspective of microfluidic bionic approaches with high efficiency for the study of tumor microenvironment and the challenges encountered in cancer research, drug discovery, and personalized therapy.

PM2.5 exposure triggers cell death through lysosomal membrane permeabilization and leads to ferroptosis insensitivity via the autophagy dysfunction/p62-KEAP1-NRF2 activation in neuronal cells.

PM2.5 exposure can be associated with the onset of neurodegenerative diseases, with oxidative stress-induced cellular homeostasis disruption and cell death as one of the main mechanisms. However, the exact cellular and molecular processes are still rarely investigated. Autophagy and KEAP1-NRF2 (Kelch-like ECH-Associating protein 1-nuclear factor erythroid 2 related factor 2) signaling pathway are two main cellular defense systems for maintaining cellular homeostasis and resisting oxidative stress. In this study, we primarily investigated the role of autophagy and KEAP1-NRF2 in regulating cell death resulting from PM2.5 exposure in mouse neuroblastoma N2a cells. Our results showed that PM2.5 exposure disrupted autophagic flux by impairing lysosomal function, including lysosomal alkalinization, increased lysosome membrane permeabilization (LMP), and Cathepsin B release. Furthermore, dysregulated autophagy enhances NRF2 activity in a p62-dependent manner, which then initiates the expression of a series of antioxidant genes and increases cellular insensitivity to ferroptosis. Meanwhile, autophagy dysfunction impairs the intracellular degradation of ferroptosis related proteins such as GPX4 and ferritin. As these proteins accumulate, cells also become less sensitive to ferroptosis. LMP-associated cell death may be the main mechanism of PM2.5-induced N2a cytotoxicity. Our results may provide insights into the mechanisms of PM2.5-induced neurotoxicity and predict effective prevention and treatment strategies.

The impacts of health insurance and resource on the burden of Alzheimer's disease and related dementias in the world population.

INTRODUCTION: The increasing prevalence of Alzheimer's disease and related dementias (ADRD) presents both a burden and an opportunity for intervention. This study aims to estimate the impacts of health insurance and resources on the burden attributed to ADRD. METHOD: Data were mainly collected from global databases for ADRD. Analysis of variance, Pearson correlation, random-effects, and fixed-effects model analyses were used in this study. RESULTS: Although the current medical expenditures were increasing and out of pocket (OOP) expenditures were declining generally in various countries, the collected global data showed an increased burden of ADRD on patients both physically and economically. Furthermore, health resources were negatively associated with disability-adjusted life years (DALY), death, and years of life lost (YLL), but were otherwise positively associated with years of life lived with disability (YLD). DISCUSSION: Effective measures should be considered to cope with the rising burden. Meanwhile, there is an urgent call for constructive and sustainable rational plans and global collaboration. HIGHLIGHTS: We explored how health insurance and resources affect Alzheimer's disease and related dementias (ADRD)-related burden. Health insurance and resources were imbalanced among four income level groups. Health insurance and resources may decrease the total ADRD burden primarily from a reduction in death-related burden. Health insurance and resources may increase disability-related burden.

Roles of Transcription Factors in the Development and Reprogramming of the Dopaminergic Neurons.

The meso-diencephalic dopaminergic (mdDA) neurons regulate various critical processes in the mammalian nervous system, including voluntary movement and a wide range of behaviors such as mood, reward, addiction, and stress. mdDA neuronal loss is linked with one of the most prominent human movement neurological disorders, Parkinson's disease (PD). How these cells die and regenerate are two of the most hotly debated PD research topics. As for the latter, it has been long known that a series of transcription factors (TFs) involves the development of mdDA neurons, specifying cell types and controlling developmental patterns. In vitro and in vivo, TFs regulate the expression of tyrosine hydroxylase, a dopamine transporter, vesicular monoamine transporter 2, and L-aromatic amino acid decarboxylase, all of which are critical for dopamine synthesis and transport in dopaminergic neurons (DA neurons). In this review, we encapsulate the molecular mechanism of TFs underlying embryonic growth and maturation of mdDA neurons and update achievements on dopaminergic cell therapy dependent on knowledge of TFs in mdDA neuronal development. We believe that a deeper understanding of the extrinsic and intrinsic factors that influence DA neurons' fate and development in the midbrain could lead to a better strategy for PD cell therapy.

Advances in NURR1-Regulated Neuroinflammation Associated with Parkinson's Disease.

Neuroinflammation plays a crucial role in the progression of neurodegenerative disorders, particularly Parkinson's disease (PD). Glial cell activation and subsequent adaptive immune involvement are neuroinflammatory features in familial and idiopathic PD, resulting in the death of dopaminergic neuron cells. An oxidative stress response, inflammatory mediator production, and immune cell recruitment and activation are all hallmarks of this activation, leading to chronic neuroinflammation and progressive neurodegeneration. Several studies in PD patients' cerebrospinal fluid and peripheral blood revealed alterations in inflammatory markers and immune cell populations that may lead to or exacerbate neuroinflammation and perpetuate the neurodegenerative process. Most of the genes causing PD are also expressed in astrocytes and microglia, converting their neuroprotective role into a pathogenic one and contributing to disease onset and progression. Nuclear receptor-related transcription factor 1 (NURR1) regulates gene expression linked to dopaminergic neuron genesis and functional maintenance. In addition to playing a key role in developing and maintaining neurotransmitter phenotypes in dopaminergic neurons, NURR1 agonists have been shown to reverse behavioral and histological abnormalities in animal PD models. NURR1 protects dopaminergic neurons from inflammation-induced degeneration, specifically attenuating neuronal death by suppressing the expression of inflammatory genes in microglia and astrocytes. This narrative review highlights the inflammatory changes in PD and the advances in NURR1-regulated neuroinflammation associated with PD. Further, we present new evidence that targeting this inflammation with a variety of potential NURR1 target therapy medications can effectively slow the progression of chronic neuroinflammation-induced PD.

Conditional deficiency of m6A methyltransferase Mettl14 in substantia nigra alters dopaminergic neuron function.

N6-Methyladenosine (m6A) is the most prevalent internal modification in messenger RNAs (mRNAs) of eukaryotes and plays a vital role in post-transcriptional regulation. Recent studies demonstrated that m6A is essential for the normal function of the central nervous system (CNS), and the deregulation of m6A leads to a series of CNS diseases. However, the functional consequences of m6A deficiency within the dopaminergic neurons of adult brain are elusive. To evaluate the necessity of m6A in dopaminergic neuron functions, we conditionally deleted Mettl14, one of the most important part of m6A methyltransferase complexes, in the substantia nigra (SN) region enriched with dopaminergic neurons. By using rotarod test, pole test, open-field test and elevated plus maze, we found that the deletion of Mettl14 in the SN region induces impaired motor function and locomotor activity. Further molecular analysis revealed that Mettl14 deletion significantly reduced the total level of m6A in the mRNA isolated from SN region. Tyrosine hydroxylase (TH), an essential enzyme for dopamine synthesis, was also down-regulated upon Mettl14 deletion, while the activation of microglia and astrocyte was enhanced. Moreover, the expression of three essential transcription factors in the regulation of TH including Nurr1, Pitx3 and En1, with abundant m6A-binding sites on their RNA 3'-untranslated regions (UTR), was significantly decreased upon Mettl14 deletion in SN. Our finding first confirmed the significance of m6A in maintaining normal dopaminergic function in the SN of adult mouse.

New therapeutics beyond amyloid-ß and tau for the treatment of Alzheimer's disease.

As the population ages, Alzheimer's disease (AD), the most common neurodegenerative disease in elderly people, will impose social and economic burdens to the world. Currently approved drugs for the treatment of AD including cholinesterase inhibitors (donepezil, rivastigmine, and galantamine) and an N-methyl-D-aspartic acid receptor antagonist (memantine) are symptomatic but poorly affect the progression of the disease. In recent decades, the concept of amyloid-ß (Aß) cascade and tau hyperphosphorylation leading to AD has dominated AD drug development. However, pharmacotherapies targeting Aß and tau have limited success. It is generally believed that AD is caused by multiple pathological processes resulting from Aß abnormality, tau phosphorylation, neuroinflammation, neurotransmitter dysregulation, and oxidative stress. In this review we updated the recent development of new therapeutics that regulate neurotransmitters, inflammation, lipid metabolism, autophagy, microbiota, circadian rhythm, and disease-modified genes for AD in preclinical research and clinical trials. It is to emphasize the importance of early diagnosis and multiple-target intervention, which may provide a promising outcome for AD treatment.

Tetrahedral DNA nanostructures functionalized by multivalent microRNA132 antisense oligonucleotides promote the differentiation of mouse embryonic stem cells into dopaminergic neurons.

MicroRNA132 (miR132) negatively regulates the differentiation of mouse embryonic stem cells (ESCs) into dopaminergic (DAergic) neurons; in contrast, antisense oligonucleotide against miR132 (miR132-ASO) effectively blocks the activity of endogenous miR132 and thereafter promotes the differentiation of DAergic neurons. However, it is difficult for miR132-ASO to enter cells without a suitable delivery system. Tetrahedral DNA nanostructures (TDNs), as a new type of DNA-based nanocarrier, have great potential in biomedical applications and even have been reported to promote stem cell differentiation. In this study, we developed functional multivalent DNA nanostructures by appending miR132-ASO motifs to three-dimensional TDNs (miR132-ASO-TDNs). Our data clearly revealed that miR132-ASO-TDNs exposure can promote the differentiation of ESCs into DAergic neurons as well as elevate DA release from differentiated DAergic neurons. MiR132-ASO-TDNs could serve as a novel biofunctional nanomaterial to improve the efficiency of DAergic neurons differentiation. Our findings may also provide a new approach for stem cell therapy against neurodegenerative diseases.

Traditional Chinese medicine for dementia.

In Western medicine, dementia refers to a spectrum of diseases affecting cognition, mental health, and physical abilities. Ancient medical literatures of traditional Chinese medicine (TCM) also recorded dementia-like symptoms, but described the disease from a totally distinct theoretical point of view. The earliest records of memory loss in ancient China can be traced back 2000 years earlier. In TCM, dementia can be attributed mainly to the Brain dystrophy, Spleen-Kidney weakness, Blood stasis, and Phlegm stagnation. Of interest, ancient Chinese physicians have proposed that dementia manifests as not only cognitive but also noncognitive symptoms including psychiatric disorders and sleep disturbance, which have been investigated widely nowadays in Western medicine. Various TCM prescriptions, herbal medicines, and acupunctures have also been proposed for dementia prevention and therapy. Some of these strategies are still used in current clinical practice. Reviewing and highlighting the unique TCM recognition of treating dementia may shed light on future dementia research.

Nurr1Cd11bcre conditional knockout mice display inflammatory injury to nigrostriatal dopaminergic neurons.

Nuclear receptor-related 1 protein (NURR1) is essential for the development and maintenance of midbrain dopaminergic (DAergic) neurons. NURR1 also protects DAergic neurons against neuroinflammation. However, it remains to be determined to what extent does NURR1 exerts its protective function through acting autonomously in the microglia. Using Cre/lox gene targeting system, we deleted Nurr1 in the microglia of Nurr1Cd11bcre conditional knockout (cKO) mice. The Nurr1Cd11bcre cKO mice displayed age-dependent motor abnormalities and increased microglial activation, but with no obvious DAergic neurodegeneration. To boost the inflammatory injury, we systemically administered endotoxin lipopolysaccharide (LPS) to Nurr1Cd11bcre mice. As expected, LPS treatment exacerbated the motor phenotypes and inflammatory reactions in Nurr1Cd11bcre cKO mice. More importantly, LPS administration caused DAergic neuron loss and α-synuclein aggregation, two pathological hallmarks of Parkinson's disease (PD). Therefore, our findings provide in vivo evidence supporting a critical protective role of NURR1 in the microglia against inflammation-induced degeneration of DAergic neurons in PD.

Research advances on L-DOPA-induced dyskinesia: from animal models to human disease.

L-3,4-dihydroxyphenylalanine (L-DOPA) was introduced about half a century ago and is still the most effective medicine for the treatment of Parkinson's disease (PD). However, such chronic treatment eventually leads to L-DOPA-induced dyskinesia (LID) on the majority of PD patients. Besides L-DOPA, dopamine agonists are able to induce dyskinesia as well. So far no drug is yet claimed to effectively curb LID, and amantadine has only a modest benefit on LID patients. Thus, understanding the molecular mechanisms behind LID is urgently needed, and developing new antiparkinsonian medications with low dyskinesia potential is necessarily required. In the last decades, several animal models have been generated for these aims. 1-Methyl-4-phenyl-1, 2, 3, 6-tetrahydropyridine (MPTP)-lesioned monkey models always considered as gold standard of PD studies are also applied well for the research of LID. Additionally, several rodent models were developed for such clinical needs. Of them, 6-hydroxydopamine (OHDA)-lesioned rats or mice exhibiting countable abnormal involuntary movements (AIMs) after L-DOPA treatments have becoming widely applicable tools for LID pathogenesis studies. Under investigating these models for years, multiple potential LID-associated genes and pathways have been innovatively identified, which largely advance the therapeutic and preventative strategies for the disease. In this review, we attempt to update the recent findings represented in LID animal models and trial studies, which may facilitate the mechanistic understanding, drug development, and clinical evaluation of this movement disorder.

Autophagy and Motor Neuron Diseases.

Motor neuron diseases (MND) are a group of fatal progressive neurodegenerative diseases, which selectively affect the motor system in the anterior horn of spinal cord, brainstem, cortex and pyramidal tract. Motor neurons could be divided into two groups, which are upper groups in the motor cortex and lower groups in the brain stem and spinal cord. Loss of lower motor neurons leads to muscle weakness, wasting and cramps. Loss of upper motor neurons leads to brisk reflexes and functional limits. There are several types of motor neuron disease: amyotrophic lateral sclerosis (ALS), progressive bulbar palsy (PBP), progressive muscular atrophy (PMA), primary lateral sclerosis (PLS). Now, the studies of autophagy in MND focus on the type of ALS, so this chapter will summarize the alteration of autophagy in motor neurons, and how that knowledge contributes to our understanding of the pathogenesis of ALS.