The “Sick-but-not-Dead” Phenomenon Applied to Catecholamine Deficiency in Neurodegenerative Diseases

2020 ◽  
Vol 40 (05) ◽  
pp. 502-514
Author(s):  
David S. Goldstein
Keyword(s):  
Lewy Body ◽  
Lewy Bodies ◽  
Dopamine Metabolism ◽  
Major Constituent ◽  
Acid Decarboxylase ◽  
Amino Acid Decarboxylase ◽  
Catecholaminergic Neurons ◽  
Disease States ◽  
Dopamine Content ◽  
Lewy Body Diseases

AbstractThe catecholamines dopamine and norepinephrine are key central neurotransmitters that participate in many neurobehavioral processes and disease states. Norepinephrine is also the main neurotransmitter mediating regulation of the circulation by the sympathetic nervous system. Several neurodegenerative disorders feature catecholamine deficiency. The most common is Parkinson's disease (PD), in which putamen dopamine content is drastically reduced. PD also entails severely decreased myocardial norepinephrine content, a feature that characterizes two other Lewy body diseases—pure autonomic failure and dementia with Lewy bodies. It is widely presumed that tissue catecholamine depletion in these conditions results directly from loss of catecholaminergic neurons; however, as highlighted in this review, there are also important functional abnormalities in extant residual catecholaminergic neurons. We refer to this as the “sick-but-not-dead” phenomenon. The malfunctions include diminished dopamine biosynthesis via tyrosine hydroxylase (TH) and L-aromatic-amino-acid decarboxylase (LAAAD), inefficient vesicular sequestration of cytoplasmic catecholamines, and attenuated neuronal reuptake via cell membrane catecholamine transporters. A unifying explanation for catecholaminergic neurodegeneration is autotoxicity exerted by 3,4-dihydroxyphenylacetaldehyde (DOPAL), an obligate intermediate in cytoplasmic dopamine metabolism. In PD, putamen DOPAL is built up with respect to dopamine, associated with a vesicular storage defect and decreased aldehyde dehydrogenase activity. Probably via spontaneous oxidation, DOPAL potently oligomerizes and forms quinone-protein adducts with (“quinonizes”) α-synuclein (AS), a major constituent in Lewy bodies, and DOPAL-induced AS oligomers impede vesicular storage. DOPAL also quinonizes numerous intracellular proteins and inhibits enzymatic activities of TH and LAAAD. Treatments targeting DOPAL formation and oxidation therefore might rescue sick-but-not-dead catecholaminergic neurons in Lewy body diseases.

scholarly journals Cross-platform transcriptional profiling identifies common and distinct molecular pathologies in Lewy body diseases

2021 ◽  
Author(s):  
Rahel Feleke ◽  
Regina H. Reynolds ◽  
Amy M. Smith ◽  
Bension Tilley ◽  
Sarah A. Gagliano Taliun ◽  
...  
Keyword(s):  
Parkinson’S Disease ◽  
Parkinson's Disease ◽  
Neurodegenerative Diseases ◽  
Lewy Body ◽  
Molecular Mechanisms ◽  
Lewy Bodies ◽  
Subsequent Development ◽  
Lewy Body Dementia ◽  
Anterior Cingulate ◽  
Lewy Body Diseases

AbstractParkinson’s disease (PD), Parkinson’s disease with dementia (PDD) and dementia with Lewy bodies (DLB) are three clinically, genetically and neuropathologically overlapping neurodegenerative diseases collectively known as the Lewy body diseases (LBDs). A variety of molecular mechanisms have been implicated in PD pathogenesis, but the mechanisms underlying PDD and DLB remain largely unknown, a knowledge gap that presents an impediment to the discovery of disease-modifying therapies. Transcriptomic profiling can contribute to addressing this gap, but remains limited in the LBDs. Here, we applied paired bulk-tissue and single-nucleus RNA-sequencing to anterior cingulate cortex samples derived from 28 individuals, including healthy controls, PD, PDD and DLB cases (n = 7 per group), to transcriptomically profile the LBDs. Using this approach, we (i) found transcriptional alterations in multiple cell types across the LBDs; (ii) discovered evidence for widespread dysregulation of RNA splicing, particularly in PDD and DLB; (iii) identified potential splicing factors, with links to other dementia-related neurodegenerative diseases, coordinating this dysregulation; and (iv) identified transcriptomic commonalities and distinctions between the LBDs that inform understanding of the relationships between these three clinical disorders. Together, these findings have important implications for the design of RNA-targeted therapies for these diseases and highlight a potential molecular “window” of therapeutic opportunity between the initial onset of PD and subsequent development of Lewy body dementia.

Influences of Catecholamine Contents on Tetrahydrobiopterin Metabolism

Pteridines ◽  
1998 ◽  
Vol 9 (1) ◽  
pp. 39-43
Author(s):  
Hiroshi Kuzuya ◽  
Hideo Sakamoto ◽  
Ko Fujita
Keyword(s):  
Nerve Growth Factor ◽  
The Other ◽  
Acid Decarboxylase ◽  
Catecholamine Metabolism ◽  
Decarboxylase Inhibitor ◽  
Amino Acid Decarboxylase ◽  
Comt Inhibitor ◽  
Dopamine Content ◽  
Pheochromocytoma Pc12 ◽  
Inhibitor Treatment

Summary The influence of changes in catecholamine metabolism on tetrahydrobiopterin biosynthesis was investigated in cultured rat pheochromocytoma PC12 cells. The increase in the cellular dopamine content after treatment with the MAO-COMT inhibitor or dopamine produced decreases in the GTP-cy-clohydrolase I (GTPCH-I) activity and total biopterin content. On the contrary, the catecholamine increase after treatment with nerve growth factor produced increases in the GTPCH -I activity and total biopterin content. On the other hand, the decrease in the dopamine content after tyrosine hydroxylase (TH) inhibitor treatment produced decreases in the GTPCH-I activity and total biopterin content, but the catecholamine decrease (the DOPA content increased about 3.4-fold) after aromatic L-amino acid decarboxylase inhibitor treatment produced a decrease in the GTPCH-I activity. These results suggest that an increase in dopamine content that is not directly related to the action of TH plays a role in down-regulation of tetrahydrobiopterin biosynthesis and that when the changes in catecholamine metabolism are strongly associated with the action of TH, tetrahydrobiopterin biosynthesis is regulated depending on the necessity for TH.

scholarly journals Motor and Nonmotor Symptoms of Parkinson’s Disease: Antagonistic Pleiotropy Phenomena Derived from α-Synuclein Evolvability?

2018 ◽  
Vol 2018 ◽  
pp. 1-6 ◽  
Author(s):  
Yoshiki Takamatsu ◽  
Masayo Fujita ◽  
Gilbert J. Ho ◽  
Ryoko Wada ◽  
Shuei Sugama ◽  
...  
Keyword(s):  
Parkinson’S Disease ◽  
Parkinson's Disease ◽  
Lewy Body ◽  
Gastrointestinal Symptoms ◽  
Lewy Bodies ◽  
Antagonistic Pleiotropy ◽  
Nonmotor Symptoms ◽  
Novel Therapy ◽  
Wide Range ◽  
Lewy Body Diseases

Lewy body diseases, such as Parkinson’s disease (PD), dementia with Lewy bodies (DLB), and multiple system atrophy (MSA), are associated with a wide range of nonmotor symptoms (NMS), including cognitive impairment, depression and anxiety, sleep disorders, gastrointestinal symptoms, and autonomic failure. The reason why such diverse and disabling NMS have not been weeded out but have persisted across evolution is unknown. As such, one possibility would be that the NMS might be somehow beneficial during development and/or reproductive stages, a possibility consistent with our recent view as to the evolvability of amyloidogenic proteins (APs) such as α-synuclein (αS) and amyloid-β (Aβ) in the brain. Based on the heterogeneity of protofibrillar AP forms in terms of structure and cytotoxicity, we recently proposed that APs might act as vehicles to deliver information regarding diverse internal and environmental stressors. Also, we defined evolvability to be an epigenetic phenomenon whereby APs are transgenerationally transmitted from parents to offspring to cope with future brain stressors in the offspring, likely benefitting the offspring. In this context, the main objective is to discuss whether NMS might be relevant to evolvability. According to this view, information regarding NMS may be transgenerationally transmitted by heterogeneous APs to offspring, preventing or attenuating the stresses related to such symptoms. On the other hand, NMS associated with Lewy body pathology might manifest through an aging-associated antagonistic pleiotropy mechanism. Given that NMS are not only specific to Lewy body diseases but also displayed in other disorders, including amyotrophic lateral sclerosis (ALS) and Huntington’s disease (HD), these conditions might share common mechanisms related to evolvability. This might give insight into novel therapy strategies based on antagonistic pleiotropy rather than on individual NMS from which to develop disease-modifying therapies.

Effects of high salt intake on dopamine production in rat kidney

1991 ◽  
Vol 260 (5) ◽  
pp. E675-E679 ◽  
Author(s):  
M. Hayashi ◽  
Y. Yamaji ◽  
W. Kitajima ◽  
T. Saruta
Keyword(s):  
Degradation Rate ◽  
Salt Intake ◽  
Rat Kidney ◽  
Dopamine Metabolism ◽  
High Salt ◽  
Acid Decarboxylase ◽  
Amino Acid Decarboxylase ◽  
High Salt Intake ◽  
Urinary Dopamine ◽  
Convoluted Tubules

To examine the origin of increased urinary dopamine excretion (UDAV) during high salt intake, we measured UDAV from the innervated (INN) or the chronically denervated (DEN) kidney in rats fed either a high-salt (HS) or low-salt (LS) diet. UDAV of DEN [3.50 +/- 0.46 ng. min-1.inulin clearance (CIN)-1] and INN (4.00 +/- 0.59 ng. min-1.CIN-1) kidneys in the HS group showed a significant increase compared with that of the respective kidney in the LS group (DEN 1.42 +/- 0.12, INN 1.44 +/- 0.09 ng.min-1.CIN-1), whereas the effect of denervation on UDAV was not significantly different between two groups. We determined aromatic L-amino acid decarboxylase (L-AADC) activity and dopamine degradation rate of microdissected proximal convoluted tubules to study the changes in dopamine metabolism. L-AADC activity in the HS group showed a significant increase compared with that in the LS group, although there was no significant change in dopamine degradation rate. We conclude that the increase in UDAV during high salt intake was mainly caused by the enhancement of extraneural dopamine production by the kidney in rats. Dopamine-producing enzyme, but not its degradation in the tubular cells, plays a role in the regulation of extraneural dopamine production.

scholarly journals Prion-like α-synuclein pathology in the brains of infants: Krabbe disease as a novel seed-competent α-synucleinopathy

2021 ◽  
Author(s):  
Christopher Hatton ◽  
Simona S. Ghanem ◽  
David Koss ◽  
Ilham Yahya Abdi ◽  
Elizabeth Gibbons ◽  
...  
Keyword(s):  
Lewy Body ◽  
Neurodegenerative Disorder ◽  
Lewy Bodies ◽  
Krabbe Disease ◽  
Biological Processes ◽  
Pathogenic Variants ◽  
Increased Risk ◽  
Galc Gene ◽  
The Brain ◽  
Lewy Body Diseases

Krabbe disease (KD) is an infantile neurodegenerative disorder resulting from pathogenic variants in the GALC gene which causes accumulation of the toxic sphingolipid psychosine. GALC variants are associated with increased risk of Lewy body diseases (LBD), an umbrella term for age-associated neurodegenerative diseases in which the protein α-synuclein aggregates into Lewy bodies. To explore whether α-synuclein in KD has pathological similarities to that in LBD, we compared post-mortem KD tissue to that of infant control cases and identified alterations to α-synuclein localisation and expression of modifications associated with LBD. To determine whether α-synuclein in KD displayed pathogenic properties associated with LBD we evaluated its seeding capacity using the real-time quaking-induced conversion assay. Strikingly, seeded aggregation of α-synuclein resulted in the formation of fibrillar aggregates similar to those observed in LBD, confirming the prion-like capacity of KD-derived α-synuclein. These observations constitute the first report of prion-like α-synuclein in the brain tissue of infants and challenge the putative view that α-synuclein pathology is merely an age-associated phenomenon, instead suggesting it can result from alterations to biological processes such as sphingolipid homeostasis. Our findings have important implications for understanding the mechanisms underlying Lewy body formation in LBD.

scholarly journals Insular cortex sub-region-dependent distribution pattern of α-synuclein immunoreactivity in Parkinson’s disease and dementia with Lewy bodies

2017 ◽  
Author(s):  
Yasmine Y. Fathy ◽  
Frank Jan de Jong ◽  
Anne-Marie van Dam ◽  
Annemieke J.M. Rozemuller ◽  
Wilma D.J. van de Berg
Keyword(s):  
Parkinson’S Disease ◽  
Parkinson's Disease ◽  
Distribution Pattern ◽  
Lewy Body ◽  
Dementia With Lewy Bodies ◽  
Lewy Bodies ◽  
Insular Cortex ◽  
Disease Stage ◽  
Incidental Lewy Body Disease ◽  
Lewy Body Diseases

AbstractThe insular cortex is a heterogeneous and widely connected brain region. It plays a role in autonomic, cognitive, emotional and somatosensory functions. Its complex and unique cytoarchitecture includes a periallocortical agranular, pro-isocortical dysgranular, and isocortical granular sub-regions. In Parkinson’s disease (PD), the insula shows α-synuclein inclusions in advanced stages of the disease and its atrophy correlates with cognitive deficits. However, little is known regarding its regional neuropathological characteristics and vulnerability in Lewy body diseases. The aim of this study is to assess the distribution pattern of α-synuclein pathology in the insular sub-regions and the selective vulnerability of its different cell types in PD and dementia with Lewy bodies (DLB). Human post-mortem insular tissues from 10 donors with incidental Lewy body disease (iLBD), PD, DLB, and age-matched controls were immunostained for α-synuclein and glial fibrillary acid protein (GFAP). Results showed that a decreasing gradient of α-synuclein pathology was present from agranular to granular sub-regions in iLBD, PD and PD with dementia (PDD) donors. The agranular insula was heavily inflicted, revealing various α-synuclein immunoreactive morphological structures, predominantly Lewy neurites (LNs), and astroglial synucleinopathy. While dysgranular and granular sub-regions showed a decreasing gradient of inclusions and more Lewy bodies (LBs) in deeper layers. In DLB, this gradient was less pronounced and severe pathology was observed in the granular insula compared to PDD and regardless of disease stage. Protoplasmic astrocytes showed α-synuclein inclusions and severe degenerative changes increasing with disease severity. While few von Economo neurons (VENs) in the fronto-insular region revealed inclusions, particularly in PDD patients. Our study reports novel findings on the differential involvement of the insular sub-regions in PD and particular involvement of the agranular sub-region, VENs and astrocytes. Thus, the differential cellular architecture of the insular sub-regions portrays the topographic variation and vulnerability to α-synuclein pathology in Lewy body diseases.

scholarly journals Lewy and his inclusion bodies: Discovery and rejection

2017 ◽  
Vol 11 (2) ◽  
pp. 198-201 ◽  
Author(s):  
Eliasz Engelhardt ◽  
Marleide da Mota Gomes
Keyword(s):  
Parkinson Disease ◽  
Lewy Body ◽  
Inclusion Bodies ◽  
Lewy Bodies ◽  
Brain Nuclei ◽  
Eosinophilic Inclusion ◽  
Paralysis Agitans ◽  
Extensive Information ◽  
The Subject ◽  
Lewy Body Diseases

ABSTRACT Fritz Jacob Heinrich Lewy described the pathology of Paralysis agitans [Parkinson disease] and was the first to identify eosinophilic inclusion bodies in neurons of certain brain nuclei, later known as Lewy bodies, the pathological signature of the Lewy body diseases. In 1912, he published his seminal study, followed soon after by an update paper, and 10 years later, in 1923, by his voluminous book, where he exhaustively described the subject. The publication provided extensive information on the pathology of Paralysis agitans, and the entirely novel finding of eosinophilic inclusion bodies, which would become widely recognized and debated in the future. His discovery was acknowledged by important researchers who even named the structure after him. However, after his last publication on the issue, inexplicably, he never mentioned his histopathological discovery again. Despite several hypotheses, the reasons that led him to neglect (reject) the structure which he so preeminently described have remained elusive.

scholarly journals Microdialysis with Radiometric Monitoring of L-[β-11C]DOPA to Assess Dopaminergic Metabolism: Effect of Inhibitors of L-Amino Acid Decarboxylase, Monoamine Oxidase, and Catechol-O-Methyltransferase on Rat Striatal Dialysate

2010 ◽  
Vol 31 (1) ◽  
pp. 124-131 ◽  
Author(s):  
Maki Okada ◽  
Ryuji Nakao ◽  
Rie Hosoi ◽  
Ming-Rong Zhang ◽  
Toshimitsu Fukumura ◽  
...  
Keyword(s):  
Amino Acid ◽  
Monoamine Oxidase ◽  
Dopamine Metabolism ◽  
Rat Striatum ◽  
Acid Decarboxylase ◽  
Comt Inhibitors ◽  
Amino Acid Decarboxylase ◽  
Metabolite Profiles ◽  
Radiometric Detection ◽  
Effect Of Inhibitors

The catecholamine, dopamine (DA), is synthesized from 3,4-dihydroxy-L-phenylalanine (L-DOPA) by aromatic L-amino acid decarboxylase (AADC). Dopamine metabolism is regulated by monoamine oxidase (MAO) and catechol- O-methyltransferase (COMT). To measure dopaminergic metabolism, we used microdialysis with radiometric detection to monitor L-[β-11C]DOPA metabolites in the extracellular space of the rat striatum. We also evaluated the effects of AADC, MAO, and COMT inhibitors on metabolite profiles. The major early species measured after administration of L-[β-11C]DOPA were [11C]3,4-dihydroxyphenylacetic acid ([11C]DOPAC) and [11C]homovanillic acid ([11C]HVA) in a 1:1 ratio, which shifted toward [11C]HVA with time. An AADC inhibitor increased the uptake of L-[β-11C]DOPA and L-3- O-methyl-[11C]DOPA and delayed the accumulation of [11C]DOPAC and [11C]HVA. The MAO and COMT inhibitors increased the production of [11C]3-methoxytyramine and [11C]DOPAC, respectively. These results reflect the L-DOPA metabolic pathway, suggesting that this method may be useful for assessing dopaminergic metabolism.

scholarly journals Cortical Lewy bodies and Aβ burden are associated with prevalence and timing of dementia in Lewy body diseases

2015 ◽  
Vol 42 (5) ◽  
pp. 436-450 ◽  
Author(s):  
C. Ruffmann ◽  
F. C. F. Calboli ◽  
I. Bravi ◽  
D. Gveric ◽  
L. K. Curry ◽  
...  
Keyword(s):  
Lewy Body ◽  
Lewy Bodies ◽  
Cortical Lewy Bodies ◽  
Lewy Body Diseases

scholarly journals Gene therapy for aromatic L-amino acid decarboxylase deficiency by MR-guided direct delivery of AAV2-AADC to midbrain dopaminergic neurons

2021 ◽  
Vol 12 (1) ◽  
Author(s):  
Toni S. Pearson ◽  
Nalin Gupta ◽  
Waldy San Sebastian ◽  
Jill Imamura-Ching ◽  
Amy Viehoever ◽  
...  
Keyword(s):  
Amino Acid ◽  
Motor Function ◽  
Viral Vector ◽  
Genetic Disorder ◽  
Dopamine Metabolism ◽  
Acid Decarboxylase ◽  
Convection Enhanced Delivery ◽  
Amino Acid Decarboxylase ◽  
Post Surgery ◽  
Midbrain Dopaminergic Neurons

AbstractAromatic L-amino acid decarboxylase (AADC) deficiency is a rare genetic disorder characterized by deficient synthesis of dopamine and serotonin. It presents in early infancy, and causes severe developmental disability and lifelong motor, behavioral, and autonomic symptoms including oculogyric crises (OGC), sleep disorder, and mood disturbance. We investigated the safety and efficacy of delivery of a viral vector expressing AADC (AAV2-hAADC) to the midbrain in children with AADC deficiency (ClinicalTrials.gov Identifier NCT02852213). Seven (7) children, aged 4–9 years underwent convection-enhanced delivery (CED) of AAV2-hAADC to the bilateral substantia nigra (SN) and ventral tegmental area (VTA) (total infusion volume: 80 µL per hemisphere) in 2 dose cohorts: 1.3 × 1011 vg (n = 3), and 4.2 × 1011 vg (n = 4). Primary aims were to demonstrate the safety of the procedure and document biomarker evidence of restoration of brain AADC activity. Secondary aims were to assess clinical improvement in symptoms and motor function. Direct bilateral infusion of AAV2-hAADC was safe, well-tolerated and achieved target coverage of 98% and 70% of the SN and VTA, respectively. Dopamine metabolism was increased in all subjects and FDOPA uptake was enhanced within the midbrain and the striatum. OGC resolved completely in 6 of 7 subjects by Month 3 post-surgery. Twelve (12) months after surgery, 6/7 subjects gained normal head control and 4/7 could sit independently. At 18 months, 2 subjects could walk with 2-hand support. Both the primary and secondary endpoints of the study were met. Midbrain gene delivery in children with AADC deficiency is feasible and safe, and leads to clinical improvements in symptoms and motor function.

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