Differential seeding and propagating efficiency of α-synuclein strains generated in different conditions

Abstract Background Accumulation of alpha-synuclein (α-syn) is a main pathological hallmark of Parkinson’s and related diseases, which are collectively known as synucleinopathies. Growing evidence has supported that the same protein can induce remarkably distinct pathological progresses and disease phenotypes, suggesting the existence of strain difference among α-syn fibrils. Previous studies have shown that α-syn pathology can propagate from the peripheral nervous system (PNS) to the central nervous system (CNS) in a “prion-like” manner. However, the difference of the propagation potency from the periphery to CNS among different α-syn strains remains unknown and the effect of different generation processes of these strains on the potency of seeding and propagation remains to be revealed in more detail. Methods Three strains of preformed α-syn fibrils (PFFs) were generated in different buffer conditions which varied in pH and ionic concentrations. The α-syn PFFs were intramuscularly (IM) injected into a novel bacterial artificial chromosome (BAC) transgenic mouse line that expresses wild-type human α-syn, and the efficiency of seeding and propagation of these PFFs from the PNS to the CNS was evaluated. Results The three strains of α-syn PFFs triggered distinct propagation patterns. The fibrils generated in mildly acidic buffer led to the most severe α-syn pathology, degeneration of motor neurons and microgliosis in the spinal cord. Conclusions The different α-syn conformers generated in different conditions exhibited strain-specific pathology and propagation patterns from the periphery to the CNS, which further supports the view that α-syn strains may be responsible for the heterogeneity of pathological features and disease progresses among synucleinopathies.

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QT Dispersion: A Predictor of Outcome Following Acute Neurologic Events

Stroke ◽

10.1161/str.32.suppl_1.343-d ◽

2001 ◽

Vol 32 (suppl_1) ◽

pp. 343-343

Author(s):

Elzbieta J Wirkowski ◽

Joseph Moonjely ◽

Todd J Cohen ◽

Stephanie M Manzella ◽

Richard H Smith ◽

...

Keyword(s):

Central Nervous System ◽

Nervous System ◽

Functional Outcome ◽

Qt Dispersion ◽

Neurological Injury ◽

Disease States ◽

Qt Intervals ◽

The Central Nervous System ◽

The Difference ◽

Adjusted Logistic Regression

P26 BACKGROUND: QT dispersion (QTD) reflects heterogeneity of myocardial repolarization, which is modulated by the central nervous system. Pervious studies have shown increased QTD to be a predictor of adverse outcome in various cardiac disease states. However, the central nervous system effects on QTD and its relation to functional outcomes have not been previously studied in patients with acute neurological events (NE). The objective of this study was to determine whether increased QTD is related to functional outcome in patients with cerebrovascular accidents (CVA) and transient ischemic attacks (TIA). METHODS: We studied 140 consecutive pts. aged 72±10 yrs. (48% male) admitted to our institution with NE from 1/98 to 4/98. QTD was calculated from admission EKG as the difference between maximum and minimum QT intervals. 120 pts. had interpretable EKGs with measurable QT intervals in at least 11 of 12 leads. Three separate functional scales (NIHSS, Barthel, and Rankin) were obtained on admission and discharge were recorded. RESULTS: QTD was higher in pts. with intracerebral hemorrhage as compared to CVA and TIA (70±15 vs. 53±27 vs. 48±31 msecs. p=0.03). Increased QTD was associated with lower functional outcome on all 3 scales (all p<0.05) and with higher mortality (p=0.02). QTD was higher in pts. with congestive heart failure (80±43 vs. 47±24 msecs. p=0.006) and carotid disease (59±32 vs. 46±27 msecs. p=0.045) as compared to those without. QTD was not associated with atrial fibrillation or coronary disease. All patients with TIA survived. On multivariate analysis, other independent predictors of poorer outcome were QTD (OR 1.35, 95% CI 1.08–1.68) and a trend towards age (OR 1.07, 95% CI 0.99–1.16). On age-adjusted logistic regression, mortality increased by an OR 1.28, 95% (CI 1.02–1.61) for every 10 msec increase in QTD. CONCLUSION: QTD is an independent predictor of functional outcome and mortality following acute neurological events. In this setting, QTD reflects acute neurological injury as well as underlying heart disease. The mechanism of these findings merits further study.

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Multifaceted roles of microRNAs: From motor neuron generation in embryos to degeneration in spinal muscular atrophy

eLife ◽

10.7554/elife.50848 ◽

2019 ◽

Vol 8 ◽

Cited By ~ 2

Author(s):

Tai-Heng Chen ◽

Jun-An Chen

Keyword(s):

Nervous System ◽

Neurodegenerative Diseases ◽

Spinal Muscular Atrophy ◽

Motor Neuron ◽

Motor Neurons ◽

Muscular Atrophy ◽

Cell Types ◽

Spinal Motor Neurons ◽

Potential Applications ◽

The Central Nervous System

Two crucial questions in neuroscience are how neurons establish individual identity in the developing nervous system and why only specific neuron subtypes are vulnerable to neurodegenerative diseases. In the central nervous system, spinal motor neurons serve as one of the best-characterized cell types for addressing these two questions. In this review, we dissect these questions by evaluating the emerging role of regulatory microRNAs in motor neuron generation in developing embryos and their potential contributions to neurodegenerative diseases such as spinal muscular atrophy (SMA). Given recent promising results from novel microRNA-based medicines, we discuss the potential applications of microRNAs for clinical assessments of SMA disease progression and treatment.

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Degeneration of skeletal muscle, peripheral nerves, and the central nervous system in transgenic mice overexpressing wild-type prion proteins

Cell ◽

10.1016/0092-8674(94)90177-5 ◽

1994 ◽

Vol 76 (1) ◽

pp. 117-129 ◽

Cited By ~ 233

Author(s):

David Westaway ◽

Stephen J. DeArmond ◽

Juliana Cayetano-Canlas ◽

Darlene Groth ◽

Dallas Foster ◽

...

Keyword(s):

Skeletal Muscle ◽

Central Nervous System ◽

Nervous System ◽

Transgenic Mice ◽

Peripheral Nerves ◽

Prion Proteins ◽

Wild Type ◽

The Central Nervous System

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Delayed development of specific thyroid hormone-regulated events in transthyretin null mice

AJP Endocrinology and Metabolism ◽

10.1152/ajpendo.00216.2012 ◽

2013 ◽

Vol 304 (1) ◽

pp. E23-E31 ◽

Cited By ~ 20

Author(s):

Julie A. Monk ◽

Natalie A. Sims ◽

Katarzyna M. Dziegielewska ◽

Roy E. Weiss ◽

Robert G. Ramsay ◽

...

Keyword(s):

Central Nervous System ◽

Cerebrospinal Fluid ◽

Nervous System ◽

Thyroid Hormone ◽

Bone Growth ◽

Circulatory System ◽

Goblet Cells ◽

Wild Type ◽

The Central Nervous System ◽

Delayed Growth

Thyroid hormones (THs) are vital for normal postnatal development. Extracellular TH distributor proteins create an intravascular reservoir of THs. Transthyretin (TTR) is a TH distributor protein in the circulatory system and is the only TH distributor protein synthesized in the central nervous system. We investigated the phenotype of TTR null mice during development. Total and free 3′,5′,3,5-tetraiodo-l-thyronine (T4) and free 3′,3,5-triiodo-l-thyronine (T3) in plasma were significantly reduced in 14-day-old (P14) TTR null mice. TTR null mice also displayed a delayed suckling-to-weaning transition, decreased muscle mass, delayed growth, and retarded longitudinal bone growth. In addition, ileums from postnatal day 0 (P0) TTR null mice displayed disordered architecture and contained fewer goblet cells than wild type. Protein concentrations in cerebrospinal fluid from P0 and P14 TTR null mice were higher than in age-matched wild-type mice. In contrast to the current literature based on analyses of adult TTR null mice, our results demonstrate that TTR has an important and nonredundant role in influencing the development of several organs.

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Central site for pressor action of blood-borne angiotensin in rat

AJP Regulatory Integrative and Comparative Physiology ◽

10.1152/ajpregu.1980.239.3.r358 ◽

1980 ◽

Vol 239 (3) ◽

pp. R358-R361 ◽

Cited By ~ 5

Author(s):

G. D. Fink ◽

J. R. Haywood ◽

W. J. Bryan ◽

W. Packwood ◽

M. J. Brody

Keyword(s):

Central Nervous System ◽

Nervous System ◽

Angiotensin Ii ◽

Pressor Response ◽

Third Ventricle ◽

Central Component ◽

The Third ◽

Electrolytic Lesions ◽

The Central Nervous System ◽

The Difference

A previous study demonstrated that the threshold dose of intra-arterial angiotensin II required to induce a pressor response in the rat was significantly lower when the drug was administered into the carotid artery than when administered into the abdominal aorta. This result was interpreted to indicate that part of the increase in arterial pressure produced by low concentrations of blood-borne angiotensin in this species was the result of an effect on structures in the central nervous system selectively accessible via the carotid vascular bed. The purpose of the present study was to establish more precisely the site of the pressor action of angiotensin within the central nervous system. The central component of the pressor effect of angiotensin was quantified as the difference in pressor responses to intracarotid and intra-aortic infusions of angiotensin II (delta c-a). In conscious rats, delta c-a was attenuated by administration of the angiotensin antagonist, saralasin, into the third cerebral ventricle. In rats with chronic electrolytic lesions of the anteroventral third ventricle (AV3V), delta c-a was abolished. Periventricular structures surrounding the third ventricle appear to mediate the central component of the pressor action of blood-borne angiotensin in the rat.

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Borna Disease Virus Accelerates Inflammation and Disease Associated with Transgenic Expression of Interleukin-12 in the Central Nervous System

Journal of Virology ◽

10.1128/jvi.76.23.12223-12232.2002 ◽

2002 ◽

Vol 76 (23) ◽

pp. 12223-12232 ◽

Cited By ~ 16

Author(s):

Susanna Freude ◽

Jürgen Hausmann ◽

Markus Hofer ◽

Ngan Pham-Mitchell ◽

Iain L. Campbell ◽

...

Keyword(s):

Central Nervous System ◽

Nervous System ◽

Transgenic Mice ◽

Disease Virus ◽

Biologically Active ◽

Interleukin 12 ◽

Wild Type ◽

Borna Disease Virus ◽

The Central Nervous System ◽

Borna Disease

ABSTRACT Targeted expression of biologically active interleukin-12 (IL-12) in astrocytes of the central nervous system (CNS) results in spontaneous neuroimmunological disease of aged mice. Borna disease virus (BDV) can readily multiply in the mouse CNS but does not trigger disease in most strains. Here we show that a large percentage of IL-12 transgenic mice developed severe ataxia within 5 to 10 weeks after infection with BDV. By contrast, no disease developed in mock-infected IL-12 transgenic and wild-type mice until 4 months of age. Neurological symptoms were rare in infected wild-type animals, and if they occurred, these were milder and appeared later. Histological analyses showed that the cerebellum of infected IL-12 transgenic mice, which is the brain region with strongest transgene expression, contained large numbers of CD4+ and CD8+ T cells as well as lower numbers of B cells, whereas other parts of the CNS showed only mild infiltration by lymphocytes. The cerebellum of diseased mice further showed severe astrogliosis, calcifications and signs of neurodegeneration. BDV antigen and nucleic acids were present in lower amounts in the inflamed cerebellum of infected transgenic mice than in the noninflamed cerebellum of infected wild-type littermates, suggesting that IL-12 or IL-12-induced cytokines exhibited antiviral activity. We propose that BDV infection accelerates the frequency by which immune cells such as lymphocytes and NK cells enter the CNS and then respond to IL-12 present in the local milieu causing disease. Our results illustrate that infection of the CNS with a virus that is benign in certain hosts can be harmful in such normally disease-resistant hosts if the tissue is unfavorably preconditioned by proinflammatory cytokines.

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Dopamine modulation of gill reflex behavior in Aplysia

Canadian Journal of Physiology and Pharmacology ◽

10.1139/y79-051 ◽

1979 ◽

Vol 57 (3) ◽

pp. 329-332 ◽

Cited By ~ 9

Author(s):

Peter Ruben ◽

Ken Lukowiak

Keyword(s):

Central Nervous System ◽

Nervous System ◽

Motor Neuron ◽

Peripheral Nervous System ◽

Motor Neurons ◽

Withdrawal Reflex ◽

Dopaminergic Pathway ◽

The Central Nervous System ◽

Dopamine Modulation

We have studied the effects of dopamine on the gill withdrawal reflex evoked by tactile siphon stimulation in the margine mollusc Aplysia. Physiological concentrations of dopamine (diluted in seawater) were perfused through the gill during siphon stimulation series. The amplitude of the reflex was potentiated by dopamine and habituation of the reflex was prevented. This occurred with no change in the activity evoked in central motor neurons. These results lead us to conclude that the dopaminergic motor neuron L9 is modulating habituation in the periphery and that the central nervous system facilitatory control of the peripheral nervous system may act via a dopaminergic pathway.

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The A30P α-synuclein mutation decreases subventricular zone proliferation

Human Molecular Genetics ◽

10.1093/hmg/ddz057 ◽

2019 ◽

Vol 28 (14) ◽

pp. 2283-2294 ◽

Cited By ~ 3

Author(s):

Xue-Ming Zhang ◽

Sabina Anwar ◽

Yongsoo Kim ◽

Jennifer Brown ◽

Isabelle Comte ◽

...

Keyword(s):

Cell Death ◽

Subventricular Zone ◽

Expression Patterns ◽

Wild Type Mouse ◽

Artificial Chromosome ◽

Alpha Synuclein ◽

Immunohistochemical Detection ◽

Wild Type ◽

Histone 3 ◽

A30p Mutation

Abstract Parkinson's disease (PD) is associated with olfactory defects in addition to dopaminergic degeneration. Dopaminergic signalling is necessary for subventricular zone (SVZ) proliferation and olfactory bulb (OB) neurogenesis. Alpha-synuclein (α-syn or Snca) modulates dopaminergic neurotransmission, and SNCA mutations cause familial PD, but how α-syn and its mutations affect adult neurogenesis is unclear. To address this, we studied a bacterial artificial chromosome transgenic mouse expressing the A30P SNCA familial PD point mutation on an Snca−/− background. We confirmed that the SNCA-A30P transgene recapitulates endogenous α-syn expression patterns and levels by immunohistochemical detection of endogenous α-syn in a wild-type mouse and transgenic SNCA-A30P α-syn protein in the forebrain. The number of SVZ stem cells (BrdU+GFAP+) was decreased in SNCA-A30P mice, whereas proliferating (phospho-histone 3+) cells were decreased in Snca−/− and even more so in SNCA-A30P mice. Similarly, SNCA-A30P mice had fewer Mash1+ transit-amplifying SVZ progenitor cells but Snca−/− mice did not. These data suggest the A30P mutation aggravates the effect of Snca loss in the SVZ. Interestingly, calbindin+ and calretinin (CalR)+ periglomerular neurons were decreased in both Snca−/−, and SNCA-A30P mice but tyrosine hydroxylase+ periglomerular OB neurons were only decreased in Snca−/− mice. Cell death decreased in the OB granule layer of Snca−/− and SNCA-A30P mice. In the same region, CalR+ numbers increased in Snca−/− and SNCA-A30P mice. Thus, α-syn loss and human A30P SNCA decrease SVZ proliferation, cell death in the OB and differentially alter interneuron numbers. Similar disruptions in human neurogenesis may contribute to the olfactory deficits, which are observed in PD.

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Integrins Have Cell-Type-Specific Roles in the Development of Motor Neuron Connectivity

Journal of Developmental Biology ◽

10.3390/jdb7030017 ◽

2019 ◽

Vol 7 (3) ◽

pp. 17 ◽

Cited By ~ 1

Author(s):

Devyn Oliver ◽

Emily Norman ◽

Heather Bates ◽

Rachel Avard ◽

Monika Rettler ◽

...

Keyword(s):

Nervous System ◽

Cell Adhesion ◽

Motor Neuron ◽

Motor Neurons ◽

Neuron Development ◽

Wild Type ◽

Cell Type ◽

C Elegans ◽

Cell Type Specific ◽

Two Phases

Formation of the nervous system requires a complex series of events including proper extension and guidance of neuronal axons and dendrites. Here we investigate the requirement for integrins, a class of transmembrane cell adhesion receptors, in regulating these processes across classes of C. elegans motor neurons. We show α integrin/ina-1 is expressed by both GABAergic and cholinergic motor neurons. Despite this, our analysis of hypomorphic ina-1(gm144) mutants indicates preferential involvement of α integrin/ina-1 in GABAergic commissural development, without obvious involvement in cholinergic commissural development. The defects in GABAergic commissures of ina-1(gm144) mutants included both premature termination and guidance errors and were reversed by expression of wild type ina-1 under control of the native ina-1 promoter. Our results also show that α integrin/ina-1 is important for proper outgrowth and guidance of commissures from both embryonic and post-embryonic born GABAergic motor neurons, indicating an ongoing requirement for integrin through two phases of GABAergic neuron development. Our findings provide insights into neuron-specific roles for integrin that would not be predicted based solely upon expression analysis.

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Transection of the Spinal Cord in Developing Xenopus Laevis

Development ◽

10.1242/dev.10.2.115 ◽

1962 ◽

Vol 10 (2) ◽

pp. 115-126

Author(s):

R. T. Sims

Keyword(s):

Spinal Cord ◽

Central Nervous System ◽

Nervous System ◽

Embryonic Development ◽

Xenopus Laevis ◽

Adult Fish ◽

Regenerative Capacity ◽

The Central Nervous System ◽

The Difference ◽

Development Proceeds

The literature on regeneration in the central nervous system of vertebrates has been reviewed exhaustively by Windle (1955, 1956). Adult fish and urodeles reestablish physiological and anatomical continuity of the spinal cord after it has been completely transected while adult anurans (Piatt & Piatt, 1958) and mammals on the whole do not. In all groups of vertebrates regeneration is more successful in the period of early embryonic development, and becomes less so as development proceeds. Experiments designed to investigate the factors responsible for this change demand an animal in which the difference in the regenerative capacity of embryonic and adult form is marked, and all stages of development are easily accessible for operative procedures. These criteria are satisfied by Anura. For this reason regeneration in the anuran central nervous system merits further investigation. After spinal cord transection in urodele larvae, Piatt (1955) found that the Mauthner axons did not regenerate although other axons around them did.

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