Severe Movement Disorder Research Articles

Loss-of-Function Mutations in FRRS1L Lead to an Epileptic-Dyskinetic Encephalopathy

Glutamatergic neurotransmission governs excitatory signaling in the mammalian brain, and abnormalities of glutamate signaling have been shown to contribute to both epilepsy and hyperkinetic movement disorders. The etiology of many severe childhood movement disorders and epilepsies remains uncharacterized. We describe a neurological disorder with epilepsy and prominent choreoathetosis caused by biallelic pathogenic variants in FRRS1L, which encodes an AMPA receptor outer-core protein. Loss of FRRS1L function attenuates AMPA-mediated currents, implicating chronic abnormalities of glutamatergic neurotransmission in this monogenic neurological disease of childhood.

Motor Performance and Physical Activity as Predictors of Prospective Falls in Community-Dwelling Older Adults by Frailty Level: Application of Wearable Technology

Background: Few studies of the association between prospective falls and sensor-based measures of motor performance and physical activity (PA) have evaluated subgroups of frailty status separately. Objective: To evaluate wearable sensor-based measures of gait, balance, and PA that are predictive of future falls in community-dwelling older adults. Methods: The Arizona Frailty Cohort Study in Tucson, Arizona, followed community-dwelling adults aged 65 years and over (without baseline cognitive deficit, severe movement disorders, or recent stroke) for falls over 6 months. Baseline measures included Fried frailty criteria: in-home and sensor-based gait (normal and fast walk), balance (bipedal eyes open and eyes closed), and spontaneous daily PA over 48 h, measured using validated wearable technologies. Results: Of the 119 participants (36% non-frail, 48% pre-frail, and 16% frail), 48 reported one or more fall (47% of non-frail, 33% of pre-frail, and 47% of frail). Although balance deficit and PA were independent fall predictors in pre-frail and frail groups, they were not sensitive to predict prospective falls in the non-frail group. Even though gait performance deteriorated as frailty increased, gait was not a predictor of prospective falls when participants were stratified based on frailty status. In pre-frail and frail participants combined, center of mass sway [odds ratio (OR) = 5.9, 95% confidence interval (CI) 2.6-13.7], PA mean walking bout duration (OR = 1.1, 95% CI 1.0-1.2), PA mean standing bout duration (OR = 0.94, 95% CI 0.91-0.99), and a fall in previous 6 months (OR = 7.3, 95% CI 1.5-36.4) were independent predictors of prospective falls (area under the curve: 0.882). Conclusion: This study suggests that independent predictors of falls are dependent on frailty status. Among sensor-derived parameters, balance deficit, longer typical walking episodes, and shorter typical standing episodes were the most sensitive predictors of prospective falls in the combined pre-frail and frail sample. Gait deficit was not a sensitive fall predictor in the context of frailty status.

Risperidone (depot) for schizophrenia.

This is a copy of an article published in the Cochrane Database of Systematic Reviews © 2016 Cochrane Collaboration Publications. © The Author(s). http://www.cochranelibrary.com/

Mutation in ATG5 reduces autophagy and leads to ataxia with developmental delay.

Autophagy is required for the homeostasis of cellular material and is proposed to be involved in many aspects of health. Defects in the autophagy pathway have been observed in neurodegenerative disorders; however, no genetically-inherited pathogenic mutations in any of the core autophagy-related (ATG) genes have been reported in human patients to date. We identified a homozygous missense mutation, changing a conserved amino acid, in ATG5 in two siblings with congenital ataxia, mental retardation, and developmental delay. The subjects' cells display a decrease in autophagy flux and defects in conjugation of ATG12 to ATG5. The homologous mutation in yeast demonstrates a 30-50% reduction of induced autophagy. Flies in which Atg5 is substituted with the mutant human ATG5 exhibit severe movement disorder, in contrast to flies expressing the wild-type human protein. Our results demonstrate the critical role of autophagy in preventing neurological diseases and maintaining neuronal health.

Telomere length in Parkinson's disease: A meta-analysis

Parkinson's disease (PD) is a common and severe movement disorder. Differences in telomere length (TL) have been reported as possible risk factors for several neuropsychiatric disorders, including PD. Results from published studies for TL in PD are inconsistent, highlighting the need for a meta-analysis. In the current work, a meta-analysis of published studies for TL in PD was carried out. PubMed, Web of Science and Google Scholar databases were used to identify relevant articles that reported TL in groups of PD patients and controls. A random-effects model was used for meta-analytical procedures. The meta-analysis included eight primary studies, derived from populations of European and Asian descent, and did not show a significant difference in TL between 956 PD patients and 1284 controls (p value: 0.246). Our results show that there is no consistent evidence of shorter telomeres in PD patients and suggest the importance of future studies on TL and PD that analyze other populations and also include assessment of TL from different brain regions.

Prevalence of Creatine Deficiency Syndromes in Children With Nonsyndromic Autism.

Creatine deficiency may play a role in the neurobiology of autism and may represent a treatable cause of autism. The goal of the study was to ascertain the prevalence of creatine deficiency syndromes (CDSs) in children with autism spectrum disorder (ASD). In a prospective multicenter study, 443 children were investigated after a confirmed diagnosis of ASD. Random spot urine screening for creatine metabolites (creatine, guanidinoacetate, creatinine, and arginine) with liquid chromatography-tandem mass spectrometry and second-tier testing with high-performance liquid chromatography methodology was followed by recall testing in 24-hour urines and confirmatory testing by Sanger-based DNA sequencing of GAMT, GATM, and SLC6A8 genes. Additional diagnostic tests included plasma creatine metabolites and in vivo brain proton magnetic resonance spectroscopy. The creatine metabolites in spot urine in the autism group were compared with 128 healthy controls controlled for age. In 443 subjects with ASD investigated for CDS, we had 0 events (event: 0, 95% confidence interval 0-0.0068), therefore with 95% confidence the prevalence of CDS is <7 in 1000 children with ASD. The autism and control groups did not vary in terms of creatine metabolites (P > .0125) in urine. Our study revealed a very low prevalence of CDS in children with nonsyndromic ASD and no obvious association between creatine metabolites and autism. Unlike our study population, we expect more frequent CDS among children with severe developmental delay, speech impairment, seizures, and movement disorders in addition to impairments in social communication, restricted interests, and repetitive behaviors.

High dose pyridoxine for the treatment of tardive dyskinesia: clinical case and review of literature.

Tardive dyskinesia (TD) is a severe delayed-onset iatrogenic movement disorder caused by dopamine receptor-blocking agents [Waln and Jankovic, 2013]. TD is a major side effect of long-term use of conventional or typical antipsychotics that can be debilitating and, in most cases, persistent [Margolese et al. 2005]. The aimless and uncontrollable movement seen in TD may involve the mouth, tongue, jaw, trunk and extremities. TD affects about 20% of individuals treated with neuroleptics [Kane and Smith, 1982]. In Nigeria, the prevalence of TD is 27% among psychiatric patients on antipsychotics [Gureje, 1989], while among other Africans and Asians, the prevalence of TD is 24% and 17.2%, respectively [Pandurangi and Aderibigbe, 1995]. Risk factors for TD include increasing age, female gender [Correll et al. 2004], alcohol and drug abuse, mood disorder and diabetes mellitus [Bhidayasiri and Boonyawairoj, 2011; Tarsy and Baldessarini, 2006]. In Asia and Africa, female gender is not a risk factor in TD, though long-term hospitalization and older age are associated with TD [Pandurangi and Aderibigbe, 1995]. The condition is associated with reduced quality-adjusted life-years (QALYs) and increased cost of healthcare [Ascher-Svanum et al. 2008; Rosenheck, 2007]. TD may be a potentially irreversible condition with most treatment modalities having less satisfactory outcome which may require complex dosing, have their own adverse effects and use for long periods that may not be desirable [Lerner et al. 2015; Waln and Jankovic, 2013]. Various treatments have been used including the use of clozapine and quietiapine [Emsley et al. 2004], dopamine-depleting agents like tetrabenazine and amantaidine [Aia et al. 2011; Kenney and Jankovi, 2006], gamma amino butyric acid (GABA) agonists like valproate and clonazepam [Aia et al. 2011; Aladed et al. 2011] and anticholinergic medications such as trihexyphenidyl [Fernandez and Friedman, 2003]. Less commonly studied agents which might be effective include pyridoxine [Waln and Jankovic, 2013]. Pyridoxine has been used experimentally in the past two decades [Lerner et al. 2015], with a number of case reports [Lerner and Liberman, 1998, 1999] and a randomized, double-blind, placebo-controlled, crossover study [Lerner et al. 2007]. A Cochrane review concluded that pyridoxine may be beneficial in reducing the severity of TD, but further studies are needed because of the limited number of existing studies and short follow-up periods [Adelufosi et al. 2015]. Here we present a case demonstrating the beneficial effect of pyridoxine in reducing the severity of TD in a patient with schizophrenia after clozapine had moderate effect on the movement disorder.

EDITORIAL (Thematic Issue: New Targets of Medical Treatment in Psychiatric Disorders)

A broader palette of safe and better-tolerated agents is available for treating people suffering from chronic schizophrenia, depressive disorders, anxiety disorder, autism spectrum disorders. However, current medical treatments are still only partially effective, and highly-prevalent psychiatric disorders continue to represent a huge personal and socio-economic burden. Most pharmacological agents sometimes induce a variety of severe movement disorders, including dystonia or dyskinesia, with an acute, subacute or more chronic time course. More extensive cerebral condition, such as the neuroleptic malignant syndrome or the serotonin syndrome may be induced by antipsychotics or selective serotonin reuptake inhibitors (SSRI). Medications commonly involve dopamine receptor blockers, antidepressants and anti-epileptics, among many others. Mechanisms underlying drug-induced movement disorders involve blockade, facilitation or imbalance of dopamine, serotonin, noradrenaline and cholinergic neurotransmission in the basal ganglia [1]. The traditional and atypical neuroleptics sometimes induce dystonic reactions, akathisia, parkinsonism, neuroleptic malignant syndrome, serotonin syndrome, tremor, hyperkinesia and movement disorders [1]. A better understanding of the impact of these drug-induced adverse effects may provide new strategies to develop novel neuroleptics with less adverse metabolic effects and to develop complementary medical therapies to patients treated with antipsychotic medication [2]. The lack of success in discovering more effective pharmacotherapy has contributed, together with many other factors, to a relative few useful findings on new drug targets for neuropsychiatric disorders.

The study of sleep disorder factors in patients with Guillain–Barré syndrome

In this study, we explore the sleep disorders and its associated factors in patients with Guillain–Barré syndrome (GBS), so as to work out appropriate interventions to promote early recovery of the patients. This study subjects included 49 patients with GBS who had been admitted to the Department of Neurology at The Affiliated Hospital of Hebei University, fulfilling National Institute of Neurological and Communicative Diseases and Stroke (NINCDS) criteria for GBS; 37 cases were male and 12 female (age: 27–68 years). Patients were evaluated once daily for two consecutive weeks. By using Wong and Baker Face Scale (WBFS) to evaluate the numbness and pain in patients, 0 points representing completely no pain and 10 points represents the most severity of the pain reactions; the same applies for numbness. The GBS Disability Scale (GBS DS) is used to evaluate the severity of GBS. The Hospital Anxiety and Depression Scale (HADS) is used to evaluate the anxiety and depression the patient is experiencing. All patients take routine EMG and sleep EEG. The sleep quality of the subjects was evaluated by the Pittsburgh Sleep Quality Index Scale (PSQI) and Richard Campbell Sleep Rating Scale. This study found that the application of ventilators, numbness, anxiety and severe limb movement disorders are the main factors causing sleep disorders. Cerebrospinal fluid (CSF) protein concentration is also associated with sleep disorders. But, no obvious abnormalities were found in sleep EEG. The application of the ventilator, numbness, anxiety and severe limb movement disorder are main factors causing sleep disorders. CSF protein concentration is also associated with sleep disorders.

Differential contributions of the globus pallidus and ventral thalamus to stimulus–response learning in humans

The ability to learn associations between stimuli, responses and rewards is a prerequisite for survival. Models of reinforcement learning suggest that the striatum, a basal ganglia input nucleus, vitally contributes to these learning processes. Our recently presented computational model predicts, first, that not only the striatum, but also the globus pallidus contributes to the learning (i.e., exploration) of stimulus–response associations based on rewards. Secondly, it predicts that the stable execution (i.e., exploitation) of well-learned associations involves further learning in the thalamus.To test these predictions, we postoperatively recorded local field potentials (LFPs) from patients that had undergone surgery for deep brain stimulation to treat severe movement disorders. Macroelectrodes were placed either in the globus pallidus or in the ventral thalamus. During recordings, patients performed a reward-based stimulus–response learning task that comprised periods of exploration and exploitation. We analyzed correlations between patients' LFP amplitudes and model-based estimates of their reward expectations and reward prediction errors.In line with our first prediction, pallidal LFP amplitudes during the presentation of rewards and reward omissions correlated with patients' reward prediction errors, suggesting pallidal access to reward-based teaching signals. Unexpectedly, the same was true for the thalamus. In further support of this prediction, pallidal LFP amplitudes during stimulus presentation correlated with patients' reward expectations during phases of low reward certainty — suggesting pallidal participation in the learning of stimulus–response associations. In line with our second prediction, correlations between thalamic stimulus-related LFP amplitudes and patients' reward expectations were significant within phases of already high reward certainty, suggesting thalamic participation in exploitation.

From splitting GLUT1 deficiency syndromes to overlapping phenotypes

IntroductionGlucose transporter type 1 deficiency syndrome (GLUT1DS) is a rare genetic disorder due to mutations or deletions in SLC2A1, resulting in impaired glucose uptake through the blood brain barrier. The classic phenotype includes pharmacoresistant epilepsy, intellectual deficiency, microcephaly and complex movement disorders, with hypoglycorrhachia, but milder phenotypes have been described (carbohydrate-responsive phenotype, dystonia and ataxia without epilepsy, paroxysmal exertion-induced dystonia).The aim of our study was to provide a comprehensive overview of GLUT1DS in a French cohort. Methods265 patients were referred to the French national laboratory for molecular screening between July 2006 and January 2012. Mutations in SLC2A1 were detected in 58 patients, with detailed clinical data available in 24, including clinical features with a focus on their epileptic pattern and electroencephalographic findings, biochemical findings and neuroimaging findings. Results53 point mutations and 5 deletions in SLC2A1 were identified. Most patients (87.5%) exhibited classic phenotype with intellectual deficiency (41.7%), epilepsy (75%) or movement disorder (29%) as initial symptoms at a medium age of 7.5 months, but diagnostic was delayed in most cases (median age at diagnostic 8 years 5 months). Sensitivity to fasting or exertion in combination with those 3 main symptoms were the main differences between mutated and negative patients (p < 0.001). Patients with myoclonic seizures (52%) evolved with more severe intellectual deficiency and movement disorders compared with those with Early Onset Absence Epilepsy (38%). Three patients evolved from a classic phenotype during early childhood to a movement disorder predominant phenotype at a late childhood/adulthood. ConclusionsOur data confirm that the classic phenotype is the most frequent in GLUT1DS. Myoclonic seizures are a distinctive feature of severe forms. However a great variability among patients and overlapping through life from milder classic phenotype to paroxysmal-prominent- movement-disorder phenotype are possible, thus making it difficult to identify definite genotype–phenotype correlations.

Mice heterozygous for cathepsin D deficiency exhibit mania-related behavior and stress-induced depression.

Mutations in cathepsin D (CTSD), an aspartic protease in the endosomal-lysosomal system, underlie congenital neuronal ceroid-lipofuscinosis (cNCL, also known as CLN10), a devastating neurodegenerative disease. CLN10 patients die within the first few days of life, and in the few patients who live into adulthood psychopathological symptoms have not been reported. Extensive neuropathology and altered neurotransmission have been reported in CTSD-deficient mice; however signs of neuropsychiatric behavior in these mice are not well characterized due to the severe movement disorder and premature death of the animal. In the present study, we show that heterozygous CTSD-deficient (CTSD HET) mice display an overall behavioral profile that is similar to human mania, including hyperlocomotion, d-amphetamine-induced hyperactivity, sleep-disturbance, and reduced anxiety-like behavior. However, under stressful conditions CTSD HET mice manifest depressive-like behavior, including anhedonia, behavioral despair, and enhanced learned helplessness. Chronic administration of lithium chloride or valproic acid, two clinically effective mood stabilizers, reverses the majority of these behavioral abnormalities. In addition, CTSD HET mice display stress-induced hypersecretion of corticosterone. These findings suggest an important role for CTSD in the regulation of mood stabilization.

Progressive Movement Disorder in Brothers Carrying a GNAO1 Mutation Responsive to Deep Brain Stimulation

GNAO1, located on chromosome 16q12.2, encodes for 1 of the heterotrimeric guanine binding proteins subunits (G proteins), specifically Gαo, which has been implicated as having an important role in brain function. GNAO1 mutations have been shown to impart oncogene properties as well as cause epileptic encephalopathy. The authors report 2 cases of brothers with a severe movement disorder and hypotonia without epilepsy who have been confirmed by whole exome sequencing to have a novel mutation in GNAO1. Their movement disorder improved significantly with deep brain stimulation.

PP12.7 – 2536: A new autosomal recessive syndrome of infolded polymicrogyria associated with a severe movement disorder

Objective To describe an 8 year old girl, with a new autosomal recessive syndrome presenting with severe dystonia and on MRI a unique pattern of infolded polymicrogyria. Methods An 8 year old girl is the product of consanguineous Arab-Moslem parents. Prenatal ultrasound demonstrated bilateral clubfeet. She achieved walking at the age of 5.5 years but has no speech. On examination she demonstrates:generalized dystonia, hypotonia with muscle wasting, clubfeet, and a a pseudobulbar syndrome with no expressive speech but good comprehension. Results MRI shows a unique pattern of bilateral infolded extensive perisylvian polymicrogyria. The findings are more prominent on the right side and do not resemble the classical patterns of polymicrogyria. Conclusion To date there is no description of this unique pattern of imaging of perisylvian polymicrogyria. The inheritance of classical bilateral perislvian polymicrogyria is mostly autosomal dominant and this syndrome is assumed to be autosomal recessive due to parental consanguinity. The severe movement disorder in our case has not been mentioned in other perisylvian syndromes.

Mutations in the mitochondrial cysteinyl-tRNA synthase gene, CARS2, lead to a severe epileptic encephalopathy and complex movement disorder

BackgroundMitochondrial disease is often suspected in cases of severe epileptic encephalopathy especially when a complex movement disorder, liver involvement and progressive developmental regression are present. Although mutations in either mitochondrial...

Mitochondrial free radical overproduction due to respiratory chain impairment in the brain of a mouse model of Rett syndrome: protective effect of CNF1

Rett syndrome (RTT) is a pervasive neurodevelopmental disorder mainly caused by mutations in the X-linked MECP2 gene associated with severe intellectual disability, movement disorders, and autistic-like behaviors. Its pathogenesis remains mostly not understood and no effective therapy is available. High circulating levels of oxidative stress markers in patients and the occurrence of oxidative brain damage in MeCP2-deficient mouse models suggest the involvement of oxidative stress in RTT pathogenesis. However, the molecular mechanism and the origin of the oxidative stress have not been elucidated. Here we demonstrate that a redox imbalance arises from aberrant mitochondrial functionality in the brain of MeCP2-308 heterozygous female mice, a condition that more closely recapitulates that of RTT patients. The marked increase in the rate of hydrogen peroxide generation in the brain of RTT mice seems mainly produced by the dysfunctional complex II of the mitochondrial respiratory chain. In addition, both membrane potential generation and mitochondrial ATP synthesis are decreased in RTT mouse brains when succinate, the complex II respiratory substrate, is used as an energy source. Respiratory chain impairment is brain area specific, owing to a decrease in either cAMP-dependent phosphorylation or protein levels of specific complex subunits. Further, we investigated whether the treatment of RTT mice with the bacterial protein CNF1, previously reported to ameliorate the neurobehavioral phenotype and brain bioenergetic markers in an RTT mouse model, exerts specific effects on brain mitochondrial function and consequently on hydrogen peroxide production. In RTT brains treated with CNF1, we observed the reactivation of respiratory chain complexes, the rescue of mitochondrial functionality, and the prevention of brain hydrogen peroxide overproduction. These results provide definitive evidence of mitochondrial reactive oxygen species overproduction in RTT mouse brain and highlight CNF1 efficacy in counteracting RTT-related mitochondrial defects.

Vowel generation for children with cerebral palsy using myocontrol of a speech synthesizer.

For children with severe cerebral palsy (CP), social and emotional interactions can be significantly limited due to impaired speech motor function. However, if it is possible to extract continuous voluntary control signals from the electromyograph (EMG) of limb muscles, then EMG may be used to drive the synthesis of intelligible speech with controllable speed, intonation and articulation. We report an important first step: the feasibility of controlling a vowel synthesizer using non-speech muscles. A classic formant-based speech synthesizer is adapted to allow the lowest two formants to be controlled by surface EMG from skeletal muscles. EMG signals are filtered using a non-linear Bayesian filtering algorithm that provides the high bandwidth and accuracy required for speech tasks. The frequencies of the first two formants determine points in a 2D plane, and vowels are targets on this plane. We focus on testing the overall feasibility of producing intelligible English vowels with myocontrol using two straightforward EMG-formant mappings. More mappings can be tested in the future to optimize the intelligibility. Vowel generation was tested on 10 healthy adults and 4 patients with dyskinetic CP. Five English vowels were generated by subjects in pseudo-random order, after only 10 min of device familiarization. The fraction of vowels correctly identified by 4 naive listeners exceeded 80% for the vowels generated by healthy adults and 57% for vowels generated by patients with CP. Our goal is a continuous “virtual voice” with personalized intonation and articulation that will restore not only the intellectual content but also the social and emotional content of speech for children and adults with severe movement disorders.

Investigating executive functions in children with severe speech and movement disorders using structured tasks.

Executive functions are the basis for goal-directed activity and include planning, monitoring, and inhibition, and language seems to play a role in the development of these functions. There is a tradition of studying executive function in both typical and atypical populations, and the present study investigates executive functions in children with severe speech and motor impairments who are communicating using communication aids with graphic symbols, letters, and/or words. There are few neuropsychological studies of children in this group and little is known about their cognitive functioning, including executive functions. It was hypothesized that aided communication would tax executive functions more than speech. Twenty-nine children using communication aids and 27 naturally speaking children participated. Structured tasks resembling everyday activities, where the action goals had to be reached through communication with a partner, were used to get information about executive functions. The children (a) directed the partner to perform actions like building a Lego tower from a model the partner could not see and (b) gave information about an object without naming it to a person who had to guess what object it was. The executive functions of planning, monitoring, and impulse control were coded from the children's on-task behavior. Both groups solved most of the tasks correctly, indicating that aided communicators are able to use language to direct another person to do a complex set of actions. Planning and lack of impulsivity was positively related to task success in both groups. The aided group completed significantly fewer tasks, spent longer time and showed more variation in performance than the comparison group. The aided communicators scored lower on planning and showed more impulsivity than the comparison group, while both groups showed an equal degree of monitoring of the work progress. The results are consistent with the hypothesis that aided language tax executive functions more than speech. The results may also indicate that aided communicators have less experience with these kinds of play activities. The findings broaden the perspective on executive functions and have implications for interventions for motor-impaired children developing aided communication.

Nigrostriatal dynein changes in A53T alpha-synuclein transgenic mice

The accumulation of misfolded a-synuclein is mechanistically linked to neurodegeneration in Parkinson’s disease (PD) and other alpha-synucleinopathies. However, how alpha-synuclein causes neurodegeneration is unresolved. Several studies have supported the involvement of dynein, the major motor for retrograde axonal transport in alpha-synuclein-dependent neurodegeneration, especially in the nigrostriatal system. Therefore, we examined the nigrostriatal dyneins in transgenic mice that overexpress human A53T alpha-synuclein and recapitulate key features of a PD-like neuronal synucleinopathy. Age-matched nontransgenic littermates were used as controls. The results demonstrated that the protein level of dynein was decreased in the striatum, whereas it was elevated in the substantia nigra. Double immunostaining results revealed that the reduction in dynein level was associated with aggregation of A53T a-synuclein in the striatum. Furthermore, we performed a quantitative analysis of motor behaviors in A53T alpha-synuclein transgenic mice and controls using a modified open field test. We demonstrated that the protein level of dynein in the striatum was significantly correlated with the motor behaviors. Together, our data indicate that dynein changes in the nigrostriatal system of A53T alpha-synuclein transgenic mice may contribute to their severe movement disorder.

Nigrostriatal dynein changes in A53T alpha-synuclein transgenic mice.

The accumulation of misfolded a-synuclein is mechanistically linked to neurodegeneration in Parkinson's disease (PD) and other alpha-synucleinopathies. However, how alpha-synuclein causes neurodegeneration is unresolved. Several studies have supported the involvement of dynein, the major motor for retrograde axonal transport in alpha-synuclein-dependent neurodegeneration, especially in the nigrostriatal system. Therefore, we examined the nigrostriatal dyneins in transgenic mice that overexpress human A53T alpha-synuclein and recapitulate key features of a PD-like neuronal synucleinopathy. Age-matched nontransgenic littermates were used as controls. The results demonstrated that the protein level of dynein was decreased in the striatum, whereas it was elevated in the substantia nigra. Double immunostaining results revealed that the reduction in dynein level was associated with aggregation of A53T a-synuclein in the striatum. Furthermore, we performed a quantitative analysis of motor behaviors in A53T alpha-synuclein transgenic mice and controls using a modified open field test. We demonstrated that the protein level of dynein in the striatum was significantly correlated with the motor behaviors. Together, our data indicate that dynein changes in the nigrostriatal system of A53T alpha-synuclein transgenic mice may contribute to their severe movement disorder.