scholarly journals Constitutive nuclear accumulation of endogenous alpha-synuclein in mice causes motor dysfunction and cortical atrophy, independent of protein aggregation.

2021 ◽  
Author(s):  
Haley M. Geertsma ◽  
Terry R Suk ◽  
Konrad M Ricke ◽  
Kyra Horsthuis ◽  
Jean-Louis A Parmasad ◽  
...  
Keyword(s):  
Alpha Synuclein ◽  
Motor Dysfunction ◽  
Cortical Atrophy ◽  
Nuclear Accumulation ◽  
Motor Deficits ◽  
Protein Overexpression ◽  
Dopaminergic Neurodegeneration ◽  
Disease Phenotypes ◽  
Experimental Systems ◽  
Biochemical Level

Background A growing body of evidence suggests that nuclear alpha-synuclein (aSyn) plays a role in the pathogenesis of Parkinson's disease (PD). However, this question has been difficult to address as controlling the localization of aSyn in experimental systems often requires protein overexpression, which results in aggregation. Methods We engineered SncaNLS mice which localize endogenous aSyn to the nucleus. We characterized these mice on a behavioral, histological, and biochemical level to determine whether the increase of nuclear aSyn is sufficient to elicit disease phenotypes. Results SncaNLS mice exhibit age-dependent motor deficits and altered gastrointestinal function. We found that these phenotypes were not linked to aSyn aggregation or phosphorylation. Through histological analyses, we observed motor cortex atrophy in the absence of midbrain dopaminergic neurodegeneration. We sampled cortical proteomes of SncaNLS mice and controls to determine the molecular underpinnings of these pathologies. Interestingly, we found several dysregulated proteins involved in dopaminergic signaling, namely Darpp-32, which we further confirmed was decreased in cortical samples of the SncaNLS mice compared to controls via immunoblotting. Conclusions These results suggest that chronic endogenous nuclear aSyn can elicit toxic phenotypes in mice, independent of its aggregation. This model raises key questions related to the mechanism of aSyn toxicity in PD and provides a new model to study an underappreciated aspect of PD pathogenesis.

scholarly journals In vivo electrophysiology of nigral and thalamic neurons in alpha-synuclein-overexpressing mice highlights differences from toxin-based models of parkinsonism

2013 ◽  
Vol 110 (12) ◽  
pp. 2792-2805 ◽  
Author(s):  
C. J. Lobb ◽  
A. K. Zaheer ◽  
Y. Smith ◽  
D. Jaeger
Keyword(s):  
Primary Motor Cortex ◽  
Alpha Synuclein ◽  
Motor Dysfunction ◽  
Motor Deficits ◽  
Dopamine Depletion ◽  
Wild Type ◽  
Beta Oscillations ◽  
Nigrostriatal Dopamine ◽  
6 Hydroxydopamine

Numerous studies have suggested that alpha-synuclein plays a prominent role in both familial and idiopathic Parkinson's disease (PD). Mice in which human alpha-synuclein is overexpressed (ASO) display progressive motor deficits and many nonmotor features of PD. However, it is unclear what in vivo pathophysiological mechanisms drive these motor deficits. It is also unknown whether previously proposed pathophysiological features (i.e., increased beta oscillations, bursting, and synchronization) described in toxin-based, nigrostriatal dopamine-depletion models are also present in ASO mice. To address these issues, we first confirmed that 5- to 6-mo-old ASO mice have robust motor dysfunction, despite the absence of significant nigrostriatal dopamine degeneration. In the same animals, we then recorded simultaneous single units and local field potentials (LFPs) in the substantia nigra pars reticulata (SNpr), the main basal ganglia output nucleus, and one of its main thalamic targets, the ventromedial nucleus, as well as LFPs in the primary motor cortex in anesthetized ASO mice and their age-matched, wild-type littermates. Neural activity was examined during slow wave activity and desynchronized cortical states, as previously described in 6-hydroxydopamine-lesioned rats. In contrast to toxin-based models, we found a small decrease, rather than an increase, in beta oscillations in the desynchronized state. Similarly, synchronized burst firing of nigral neurons observed in toxin-based models was not observed in ASO mice. Instead, we found more subtle changes in pauses of SNpr firing compared with wild-type control mice. Our results suggest that the pathophysiology underlying motor dysfunction in ASO mice is distinctly different from striatal dopamine-depletion models of parkinsonism.

scholarly journals Deleting Mecp2 from the entire cerebellum rather than its neuronal subtypes causes a delay in motor learning in mice

2020 ◽  
Author(s):  
Nathan P. Achilly ◽  
Lingjie He ◽  
Olivia A. Kim ◽  
Shogo Ohmae ◽  
Gregory J. Wojaczynski ◽  
...  
Keyword(s):  
Motor Learning ◽  
Rett Syndrome ◽  
Cell Types ◽  
Brain Regions ◽  
Motor Dysfunction ◽  
Motor Deficits ◽  
Cerebellar Dysfunction ◽  
Disease Phenotypes ◽  
Cerebellar Cell ◽  
The Many

ABSTRACTRett syndrome is a devastating childhood neurological disorder caused by mutations in MECP2. Of the many symptoms, motor deterioration is a significant problem for patients. In mice, deleting Mecp2 from the cortex or basal ganglia causes motor dysfunction, hypoactivity, and tremor, which are abnormalities observed in patients. However, little is known about the consequences of deleting Mecp2 from the cerebellum, a brain region critical for motor function. Here we show that deleting Mecp2 from the entire cerebellum, but not from individual cerebellar cell types, causes a delay in motor learning that is overcome by additional training. We also observed irregular firing rates of Purkinje cells and transcriptional misregulation within the cerebellum of knockout mice. These findings demonstrate that the motor deficits present in Rett syndrome arise, in part, from cerebellar dysfunction. For Rett syndrome as well as other neurodevelopmental disorders, our results highlight the importance of understanding which brain regions contribute to disease phenotypes.

scholarly journals Deleting Mecp2 from the cerebellum rather than its neuronal subtypes causes a delay in motor learning in mice

eLife ◽  
2021 ◽  
Vol 10 ◽  
Author(s):  
Nathan P Achilly ◽  
Ling-jie He ◽  
Olivia A Kim ◽  
Shogo Ohmae ◽  
Gregory J Wojaczynski ◽  
...  
Keyword(s):  
Motor Learning ◽  
Rett Syndrome ◽  
Neurodevelopmental Disorders ◽  
Brain Regions ◽  
Motor Dysfunction ◽  
Motor Deficits ◽  
Cerebellar Dysfunction ◽  
Firing Rates ◽  
Disease Phenotypes ◽  
The Many

Rett syndrome is a devastating childhood neurological disorder caused by mutations in MECP2. Of the many symptoms, motor deterioration is a significant problem for patients. In mice, deleting Mecp2 from the cortex or basal ganglia causes motor dysfunction, hypoactivity, and tremor, which are abnormalities observed in patients. Little is known about the function of Mecp2 in the cerebellum, a brain region critical for motor function. Here we show that deleting Mecp2 from the cerebellum, but not from its neuronal subtypes, causes a delay in motor learning that is overcome by additional training. We observed irregular firing rates of Purkinje cells and altered heterochromatin architecture within the cerebellum of knockout mice. These findings demonstrate that the motor deficits present in Rett syndrome arise, in part, from cerebellar dysfunction. For Rett syndrome and other neurodevelopmental disorders, our results highlight the importance of understanding which brain regions contribute to disease phenotypes.

Aids Dementia Complex

1999 ◽  
Vol 5 (S2) ◽  
pp. 1090-1091
Author(s):  
S.J. DeArmond
Keyword(s):  
White Matter ◽  
Motor Dysfunction ◽  
Aids Dementia Complex ◽  
World Health ◽  
Cortical Atrophy ◽  
Motor Deficit ◽  
Motor Deficits ◽  
Aids Patients ◽  
Aids Dementia ◽  
Hiv 1

The World Health Organization estimates by the year 2000 that the cumulative total of HIV-1 infected adults and children will be about 30 million worldwide. Disease of the central nervous system (CNS) in association with AIDS is common. 20-30% of AIDS patients will develop varying degrees of cognitive and motor deficits designated the “AIDS dementia Complex (ADC)” or “HIV-1-associated cognitive/motor deficit”. Progression of symptoms is usually slow and irregular. In the end-stage, the patient is severely impaired with mutism, incontinence and prominent motor impairment. Neuroradiologic studies show generalized cortical atrophy and diffuse white matter changes. HIV can be cultured from the CSF. Neurologic involvement in pediatric AIDS is very common with CNS complications usually occurring within the first two postnatal years. Given the severeness of the dementia and motor dysfunction in ADC, one is struck by the paucity of neuropathological features. Hematoxylin and eosin stained sections reveal only three neuropathological features. First, there are small numbers of microglial nodules scattered in the white matter and sometimes in grey matter (Fig. 1). However, microglial nodules occur in virtually all viral infections of the CNS, including CMV micronodular encephalitis in AIDS patients.

scholarly journals Protein kinase CK2 alpha prime and alpha-synuclein constitute a key regulatory pathway in Huntington’s disease

2020 ◽  
Author(s):  
Dahyun Yu ◽  
Nicole Zarate ◽  
Francesco Cuccu ◽  
Johnny S. Yue ◽  
Taylor G. Brown ◽  
...  
Keyword(s):  
Protein Kinase ◽  
Huntington's Disease ◽  
Huntington’S Disease ◽  
Protein Kinase Ck2 ◽  
Neurodegenerative Disorder ◽  
Alpha Synuclein ◽  
Motor Dysfunction ◽  
Motor Deficits ◽  
Striatal Neurons ◽  
Kinase Ck2

SummaryHuntington’s Disease (HD) is a neurodegenerative disorder caused by a polyglutamine expansion in the HTT protein. This mutation causes HTT misfolding and aggregation, preferentially affecting neurons of the basal ganglia. Other aggregation-prone proteins like alpha-synuclein (α-syn), mostly associated with Parkinson’s disease (PD), has recently been involved in motor deficits in HD, but its mechanism of action is unknown. Here we showed that α-syn serine 129 phosphorylation (α-syn-pS129), a posttranslational modification linked to α-synucleinopathy, is highly phosphorylated in the brain of symptomatic zQ175 HD mice. We demonstrated that such phosphorylation is mediated by Protein Kinase CK2 alpha prime (CK2α’), which is preferentially induced in striatal neurons in HD. Knocking out one allele of CK2α’ in zQ175 mice decreased α-syn-pS129 in the striatum and ameliorated several HD-like symptoms including neuroinflammation, transcriptional alterations, excitatory synaptic transmission deficits and motor dysfunction. Our data suggests CK2α’-mediated synucleinopathy as a key molecular mechanism of neurodegeneration in HD.

scholarly journals Motor Dysfunction in REM Sleep Behavior Disorder: A Rehabilitation Framework for Prodromal Synucleinopathy

2021 ◽  
pp. 154596832110112
Author(s):  
Rebekah L. S. Summers ◽  
Miriam R. Rafferty ◽  
Michael J. Howell ◽  
Colum D. MacKinnon
Keyword(s):  
Rem Sleep ◽  
Motor System ◽  
Clinical Care ◽  
Rem Sleep Behavior Disorder ◽  
Behavior Disorder ◽  
Motor Dysfunction ◽  
Motor Deficits ◽  
Sleep Behavior ◽  
Early Exercise ◽  
Extrapyramidal Signs

Parkinson disease (PD) and other related diseases with α-synuclein pathology are associated with a long prodromal or preclinical stage of disease. Predictive models based on diagnosis of idiopathic rapid eye movement (REM) sleep behavior disorder (iRBD) make it possible to identify people in the prodromal stage of synucleinopathy who have a high probability of future disease and provide an opportunity to implement neuroprotective therapies. However, rehabilitation providers may be unaware of iRBD and the motor abnormalities that indicate early motor system dysfunction related to α-synuclein pathology. Furthermore, there is no existing rehabilitation framework to guide early interventions for people with iRBD. The purpose of this work is to (1) review extrapyramidal signs of motor system dysfunction in people with iRBD and (2) propose a framework for early protective or preventive therapies in prodromal synucleinopathy using iRBD as a predictive marker. Longitudinal and cross-sectional studies indicate that the earliest emerging motor deficits in iRBD are bradykinesia, deficits performing activities of daily living, and abnormalities in speech, gait, and posture. These deficits may emerge up to 12 years before a diagnosis of synucleinopathy. The proposed rehabilitation framework for iRBD includes early exercise-based interventions of aerobic exercise, progressive resistance training, and multimodal exercise with rehabilitation consultations to address exercise prescription, progression, and monitoring. This rehabilitation framework may be used to implement neuroprotective, multidisciplinary, and proactive clinical care in people with a high likelihood of conversion to PD, dementia with Lewy bodies, or multiple systems atrophy.

scholarly journals Contributions of PCSS, CISS, and VOMS for Identifying Vestibular/Ocular Motor Deficits in Pediatric Concussions

2021 ◽  
pp. 194173812199411
Author(s):  
Rishi D. Patel ◽  
Cynthia R. LaBella
Keyword(s):  
Sports Medicine ◽  
Tertiary Care ◽  
Motor Dysfunction ◽  
Motor Deficits ◽  
Ocular Motor ◽  
Symptom Scale ◽  
Level Of Evidence ◽  
Cross Sectional ◽  
Visual Problems ◽  
Clinical Tools

Background: Vestibular/ocular motor dysfunction can occur in pediatric concussions, which can impair reading, learning, and participation in athletics. This study evaluated 3 clinical tools for identifying postconcussion vestibular/ocular motor dysfunction: (1) Post-Concussion Symptom Scale (PCSS), (2) Convergence Insufficiency Symptom Survey (CISS), and (3) Vestibular/Ocular Motor Screening (VOMS). Hypothesis: Evaluating vestibular/ocular motor dysfunction with multiple clinical tools will capture more symptomatic patients than any 1 tool alone. Study Design: Cross-sectional data from a prospective cohort study. Level of Evidence: Level 4. Methods: Patients were between 8 and 17 years old and seen in a tertiary care pediatric sports medicine clinic between August 2014 and February 2018. Data were collected from initial visit and included VOMS, PCSS, and CISS. Descriptive statistics, Pearson’s correlations, and logistic regressions were used to describe relationships between clinical tools. Results: Of the 156 patients (55.1% female; 14.35 ± 2.26 years old) included, this study identified 129 (82.7%) with vestibular/ocular motor dysfunction. Of these 129, 65 (50.4%) reported “visual problems” on PCSS, 93 (72.1%) had abnormal CISS, and 99 (76.7%) had abnormal VOMS. Together, VOMS and CISS identified 64 (49.6%) patients without reported “visual problems” on PCSS. Higher total PCSS scores predicted abnormal CISS (odds ratio [OR], = 1.11; 95% CI, 1.07-1.17) and abnormal VOMS (OR, 1.03; 95% CI, 1.01-1.06). “Visual problems” on PCSS did not predict abnormal CISS or VOMS. Conclusions: Vestibular/ocular motor dysfunction were identified in nearly 83% of study subjects when PCSS, CISS, and VOMS are used together. Clinical Relevance: These results suggest adding CISS and VOMS to the clinical evaluation of concussions can help clinicians identify post-concussion vestibular/ocular motor dysfunction.

scholarly journals Alpha-synuclein from patient Lewy bodies exhibits distinct pathological activity that can be propagated in vitro

2021 ◽  
Vol 9 (1) ◽  
Author(s):  
Nicholas P. Marotta ◽  
Jahan Ara ◽  
Norihito Uemura ◽  
Marshall G. Lougee ◽  
Emily S. Meymand ◽  
...  
Keyword(s):  
Cellular Response ◽  
Amyloid Fibrils ◽  
Cultured Cells ◽  
Biological Activities ◽  
Lewy Bodies ◽  
Alpha Synuclein ◽  
Biological Behavior ◽  
Motor Deficits ◽  
Original Material

AbstractLewy bodies (LBs) are complex, intracellular inclusions that are common pathological features of many neurodegenerative diseases. They consist largely of aggregated forms of the protein alpha-Synuclein (α-Syn), which misfolds to give rise to beta-sheet rich amyloid fibrils. The aggregation of monomers into fibrils occurs readily in vitro and pre-formed fibrils (PFFs) generated from recombinant α-Syn monomers are the basis of many models of LB diseases. These α-Syn PFFs recapitulate many pathological phenotypes in both cultured cells and animal models including the formation of α-Syn rich, insoluble aggregates, neuron loss, and motor deficits. However, it is not clear how closely α-Syn PFFs recapitulate the biological behavior of LB aggregates isolated directly from patients. Direct interrogation of the cellular response to LB-derived α-Syn has thus far been limited. Here we demonstrate that α-Syn aggregates derived from LB disease patients induce pathology characterized by a prevalence of large somatic inclusions that is distinct from the primarily neuritic pathology induced by α-Syn PFFs in our cultured neuron model. Moreover, these LB-derived aggregates can be amplified in vitro using recombinant α-Syn to generate aggregates that maintain the unique, somatic pathological phenotype of the original material. Amplified LB aggregates also showed greater uptake in cultured neurons and greater pathological burden and more rapid pathological spread in injected mouse brains, compared to α-Syn PFFs. Our work indicates that LB-derived α-Syn from diseased brains represents a distinct conformation species with unique biological activities that has not been previously observed in fully recombinant α-Syn aggregates and demonstrate a new strategy for improving upon α-Syn PFF models of synucleinopathies using amplified LBs.

scholarly journals Chronic and progressive deficits after a single closed head injury in mice

2021 ◽  
Author(s):  
Siobhan Lawless ◽  
David Havlicek ◽  
Craig Kelley ◽  
Elena Nikulina ◽  
Peter Bergold
Keyword(s):  
Head Injury ◽  
Behavioral Outcomes ◽  
Closed Head Injury ◽  
Acute Injury ◽  
Cortical Atrophy ◽  
Motor Deficits ◽  
Markerless Tracking ◽  
Closed Head ◽  
Progressive Disorder ◽  
Progressive Motor Deficits

Background: Acute injury following brain trauma may evolve into a chronic and progressive disorder. Assessment of chronic consequences of TBI must distinguish between effects of age and injury. Methods: C57BL/6 mice receive single closed head injury (CHI) and are analyzed at 14DPI or 180DPI for cortical atrophy and 7DPI or 180DPI for behavioral outcomes. Results: CHI induces ipsilesional atrophy at 14DPI that increases 180 DPI due to an effect of age. On open field, injured mice develop a turn bias at 180DPI not present at 7DPI. On rotarod, injured mice have shorter latencies at 7DPI, but not at 180DPI due to worsening performance of aging uninjured mice. On beam walk, both groups at 180DPI more slowly traverse a 2cm and 1cm beam than at 7DPI. Foot-faults show no significant effects of age or injury. Limb position was assessed using DeeplabcutTM markerless tracking followed by computation of absition (integral of limb displacement over time) using custom Python scripts. On the 2cm beam, age increased absition in all limbs of uninjured mice and both forelimbs of injured mice. Injury increased left hindlimb absition at 7DPI. On the 1cm beam both forelimbs and the left hindlimb of injured mice at 180DPI have larger absition than uninjured mice at 180DPI or injured mice at 7DPI. These data suggest chronic and progressive motor deficits of injured mice at 180DPI. Conclusions: A single impact produces ipsilesional cortical atrophy and chronic and progressive motor deficits. Quantitative behavioral analysis reveals deficits not seen using standard outcomes.

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