Dataset Information

Loss of MINAR2 impairs motor function and causes Parkinson's disease-like symptoms in mice.

ABSTRACT: Parkinson's disease is the second most common human neurodegenerative disease. Motor control impairment represents a key clinical hallmark and primary clinical symptom of the disease, which is further characterized by the progressive loss of dopaminergic neurons in the substantia nigra pars compacta and the accumulation of ?-synuclein aggregations. We have identified major intrinsically disordered NOTCH2-associated receptor 2 encoded by KIAA1024L, a previously uncharacterized protein that is highly conserved in humans and other species. In this study, we demonstrate that major intrinsically disordered NOTCH2-associated receptor 2 expression is significantly down-regulated in the frontal lobe brain of patients with Lewy body dementia. Major intrinsically disordered NOTCH2-associated receptor 2 is predominantly expressed in brain tissue and is particularly prominent in the midbrain. Major intrinsically disordered NOTCH2-associated receptor 2 interacts with neurogenic locus notch homologue protein 2 and is localized at the endoplasmic reticulum compartments. We generated major intrinsically disordered NOTCH2-associated receptor 2 knockout mouse and demonstrated that the loss of major intrinsically disordered NOTCH2-associated receptor 2 in mouse results in severe motor deficits such as rigidity and bradykinesia, gait abnormalities, reduced spontaneous locomotor and exploratory behaviour, symptoms that are highly similar to those observed in human Parkinson's spectrum disorders. Analysis of the major intrinsically disordered NOTCH2-associated receptor 2 knockout mice brain revealed significant anomalies in neuronal function and appearance including the loss of tyrosine hydroxylase-positive neurons in the pars compacta, which was accompanied by an up-regulation in ?-synuclein protein expression. Taken together, these data demonstrate a previously unknown function for major intrinsically disordered NOTCH2-associated receptor 2 in the pathogenesis of Parkinson's spectrum disorders.

SUBMITTER: Ho RX

PROVIDER: S-EPMC7425422 | biostudies-literature | 2020

REPOSITORIES: biostudies-literature

ACCESS DATA

Publications

Loss of MINAR2 impairs motor function and causes Parkinson's disease-like symptoms in mice.

Ho Rachel Xi-Yeen RX Amraei Razie R De La Cena Kyle Oliver Corcino KOC Sutherland Evan G EG Mortazavi Farzad F Stein Thor T Chitalia Vipul V Rahimi Nader N

Brain communications 20200421 1

Parkinson's disease is the second most common human neurodegenerative disease. Motor control impairment represents a key clinical hallmark and primary clinical symptom of the disease, which is further characterized by the progressive loss of dopaminergic neurons in the substantia nigra pars compacta and the accumulation of α-synuclein aggregations. We have identified major intrinsically disordered NOTCH2-associated receptor 2 encoded by <i>KIAA1024L</i>, a previously uncharacterized protein that ...[more]

PMID: 32954300

Similar Datasets

Project description:Deep brain stimulation (DBS) is a surgical procedure that has been shown effective in improving the cardinal motor signs of advanced Parkinson's disease, however, declines in cognitive function have been associated with bilateral subthalamic nucleus (STN) DBS. Despite the fact that most activities of daily living clearly have motor and cognitive components performed simultaneously, postoperative assessments of cognitive and motor function occur, in general, in isolation of one another. The primary aim of this study was to determine the effects of unilateral and bilateral STN DBS on upper extremity motor function and cognitive performance under single- and dual-task conditions in advanced Parkinson's disease patients. Data were collected from eight advanced Parkinson's disease patients between the ages of 48 and 70 years (mean 56.5) who had bilaterally placed STN stimulators. Stimulation parameters for DBS devices were optimized clinically and were stable for at least 6 months prior to study participation. Data were collected while patients were Off anti-parkinsonian medications under three stimulation conditions: Off stimulation, unilateral DBS and bilateral DBS. In each stimulation condition patients performed a cognitive (n-back task) and motor (force tracking) task under single- and dual-task conditions. During dual-task conditions, patients performed the n-back and force-maintenance task simultaneously. Under relatively simple dual-task conditions there were no differences in cognitive or motor performance under unilateral and bilateral stimulation. As dual-task complexity increased, cognitive and motor performance was significantly worse with bilateral compared with unilateral stimulation. In the most complex dual-task condition (i.e. 2-back + force tracking), bilateral stimulation resulted in a level of motor performance that was similar to the Off stimulation condition. Significant declines in cognitive and motor function under modest dual-task conditions with bilateral but not with unilateral STN DBS suggest that unilateral procedures may be an alternative to bilateral DBS for some patients, in particular, those with asymmetric symptomology. From a clinical perspective, these results underscore the need to assess cognitive and motor function simultaneously during DBS programming as these conditions may better reflect the context in which daily activities are performed.

Project description:BackgroundParkinson's disease (PD), the most common neurodegenerative movement disorder, is characterized by dopaminergic nigrostriatal neuron loss and brain accumulation of Lewy bodies, protein aggregates mainly composed of α-synuclein. We reported that mice deficient for NF-κB/c-Rel (c-rel-/-) develop a late-onset parkinsonism. At 18 months of age, c-rel-/- mice showed nigrostriatal degeneration and accumulation of α-synuclein aggregates associated with a motor impairment responsive to L-DOPA administration. Being c-Rel protein a transcriptional regulator for mitochondrial anti-oxidant and antiapoptotic factors, it has been inferred that its deficiency may affect the resilience of "energy demanding" nigral dopaminergic neurons to the aging process. PD patients manifest a prodromal syndrome that includes olfactory and gastrointestinal dysfunctions years before the frank degeneration of nigrostriatal neurons and appearance of motor symptoms. According to the Braak staging, the onset of non-motor and motor symptoms relates to progressive ascendant diffusion of α-synuclein pathology in the brain. The aim of this study was to identify whether c-rel-/- deficiency is associated with the onset of premotor signs of PD and spatio-temporal progression of cerebral α-synuclein deposition.MethodsIntestinal and olfactory functions, intestine and brain α-synuclein deposition as well as striatal alterations, were assessed in c-rel-/- and control mice from 2 to 18 months of age.ResultsFrom 2 months of age, c-rel-/- mice displayed intestinal constipation and increasing olfactory impairment. At 2 months, c-rel-/- mice exhibited a mild α-synuclein accumulation in the distal colon. Moreover, they developed an age-dependent deposition of fibrillary α-synuclein that, starting at 5 months from the olfactory bulbs, dorsal motor nucleus of vagus and locus coeruleus, reached the substantia nigra at 12 months. At this age, the α-synuclein pathology associated with a drop of dopamine transporter in the striatum that anticipated by 6 months the axonal degeneration. From 12 months onwards oxidative/nitrosative stress developed in the striatum in parallel with altered expression of mitochondrial homeostasis regulators in the substantia nigra.ConclusionsIn c-rel-/- mice, reproducing a parkinsonian progressive pathology with non-motor and motor symptoms, a Braak-like pattern of brain ascending α-synuclein deposition occurs. The peculiar phenotype of c-rel-/- mice envisages a potential contribution of c-Rel dysregulation to the pathogenesis of PD.

Project description:Parkinson's disease (PD) is characterized by motor symptoms and a loss of dopaminergic neurons, as well as a variety of non-motor symptoms, including constipation, depression, and anxiety. Recently, evidence has also accumulated for a link between gut microbiota and PD. Most PD patients are on dopamine replacement therapy, primarily a combination of L-DOPA and carbidopa; however, the effect of these medications on the microbiota and non-motor symptoms in PD is still unclear. In this study, we explored the effects of chronic oral treatment with L-DOPA plus carbidopa (LDCD) on the gut microbiota and non-motor symptoms in males of a transgenic mouse model of PD (dbl-PAC-Tg(SNCAA53T);Snca-/-). To further test whether the effects of these PD medications were mediated by the gut microbiota, oral antibiotic treatment (Abx; vancomycin and neomycin) was included both with and without concurrent LDCD treatment. Post-treatment, the gastrointestinal, motor, and behavioral phenotypes were profiled, and fecal, ileal, and jejunal samples were analyzed for gut microbiota composition by 16S sequencing. LDCD treatment was found to improve symptoms of constipation and depression in this model, concurrent with increases in Turicibacter abundance in the ileum. Abx treatment worsened the symptoms of constipation, possibly through decreased levels of short-chain fatty acids and disrupted gut barrier function. LDCD + Abx treatment showed an interaction effect on behavioral symptoms that was also associated with ileal Turicibacter levels. This study demonstrates that, in a mouse model, PD medications and antibiotics affect PD-related non-motor symptoms potentially via the gut microbiota.IMPORTANCEThe motor symptoms of Parkinson's disease (PD) are caused by a loss of dopamine-producing neurons and are commonly treated with dopamine replacement therapy (L-DOPA plus carbidopa). PD has also been associated with altered gut microbiota composition. However, the effects of these PD medications on PD-related non-motor symptoms and the gut microbiota have not been well characterized. This study uses a transgenic mouse model of PD to help resolve medication-induced microbiota alterations from those that are potentially disease relevant within a PD context, and explores how long-term treatment may interact with the gut microbiota to impact non-motor symptoms.

Dataset Information

Loss of MINAR2 impairs motor function and causes Parkinson's disease-like symptoms in mice.

Publications

Loss of MINAR2 impairs motor function and causes Parkinson's disease-like symptoms in mice.

Similar Datasets

OmicsDI is part of the ELIXIR infrastructure

Tweets