Gastrointestinal disorders in Parkinson’s disease and other Lewy body diseases

Abstract Parkinson’s disease (PD) is pathologically characterized by the abnormal accumulation of α-synuclein fibrils (Lewy bodies) in the substantia nigra and other brain regions, although the role of Lewy bodies remains elusive. Constipation usually precedes the motor symptoms in PD, which is in accordance with the notion that α-synuclein fibrils start from the intestinal neural plexus and ascend to the brain in at least half of PD patients. The gut microbiota is likely to be involved in intestinal and brain pathologies. Analyses of the gut microbiota in PD, rapid-eye-movement sleep behavior disorder, and dementia with Lewy bodies suggest three pathological pathways. First, Akkermansia, which is increased in PD, degrades the intestinal mucus layer and increases intestinal permeability, which triggers inflammation and oxidative stress in the intestinal neural plexus. Second, decreased short-chain fatty acids (SCFAs)-producing bacteria in PD reduce the number of regulatory T cells. Third, SCFAs also aggravate microglial activation with an unelucidated pathway. In addition, in dementia with Lewy bodies (DLB), which is another form of α-synucleinopathies, increased genera, Ruminococcus torques and Collinsella, may mitigate neuroinflammation in the substantia nigra by increasing secondary bile acids. Interventions for the gut microbiota and their metabolites may potentially delay or mitigate the development and progression of PD and other Lewy body diseases

Role of Numb in Dendritic Spine Development with a Cdc42 GEF Intersectin and EphB2

Numb has been implicated in cortical neurogenesis during nervous system development, as a result of its asymmetric partitioning and antagonizing Notch signaling. Recent studies have revealed that Numb functions in clathrin-dependent endocytosis by binding to the AP-2 complex. Numb is also expressed in postmitotic neurons and plays a role in axonal growth. However, the functions of Numb in later stages of neuronal development remain unknown. Here, we report that Numb specifically localizes to dendritic spines in cultured hippocampal neurons and is implicated in dendritic spine morphogenesis, partially through the direct interaction with intersectin, a Cdc42 guanine nucleotide exchange factor (GEF). Intersectin functions as a multidomain adaptor for proteins involved in endocytosis and cytoskeletal regulation. Numb enhanced the GEF activity of intersectin toward Cdc42 in vivo. Expression of Numb or intersectin caused the elongation of spine neck, whereas knockdown of Numb and Numb-like decreased the protrusion density and its length. Furthermore, Numb formed a complex with EphB2 receptor-type tyrosine kinase and NMDA-type glutamate receptors. Knockdown of Numb suppressed the ephrin-B1-induced spine development and maturation. These results highlight a role of Numb for dendritic spine development and synaptic functions with intersectin and EphB2

Discovery of long-range inhibitory signaling to ensure single axon formation

A long-standing question in neurodevelopment is how neurons develop a single axon and multiple dendrites from common immature neurites. Long-range inhibitory signaling from the growing axon is hypothesized to prevent outgrowth of other immature neurites and to differentiate them into dendrites, but the existence and nature of this inhibitory signaling remains unknown. Here, we demonstrate that axonal growth triggered by neurotrophin-3 remotely inhibits neurite outgrowth through long-range Ca[2+] waves, which are delivered from the growing axon to the cell body. These Ca[2+] waves increase RhoA activity in the cell body through calcium/calmodulin-dependent protein kinase I. Optogenetic control of Rho-kinase combined with computational modeling reveals that active Rho-kinase diffuses to growing other immature neurites and inhibits their outgrowth. Mechanistically, calmodulin-dependent protein kinase I phosphorylates a RhoA-specific GEF, GEF-H1, whose phosphorylation enhances its GEF activity. Thus, our results reveal that long-range inhibitory signaling mediated by Ca[2+] wave is responsible for neuronal polarization

A clinical approach to brown adipose tissue in the para-aortic area of the human thorax.

BACKGROUND:Human thoracic brown adipose tissue (BAT), composed of several subdivisions, is a well-known target organ of many clinical studies; however, the functional contribution of each part of human thoracic BAT remains unknown. The present study analyzed the significance of each part of human thoracic BAT in the association between regional distribution, cellularity, and factors involved in the functional regulation of thoracic BAT. METHODS:We analyzed 1550 healthy adults who underwent medical check-ups by positron-emission tomography and computed tomography (PET-CT) imaging, 8 cadavers, and 78 autopsy cases in an observational study. We first characterized the difference between the mediastinum and the supraclavicular areas using counts of BAT detection and conditions based on PET-CT outcomes. The measurable important area was then subjected to systematic anatomical and immunohistochemical analyses using anti-uncoupling protein 1 (UCP1) antibody to characterize the cellularity in association with age and sex. RESULTS:In PET-CT scanning, the main site of thoracic BAT was the mediastinum rather than the supraclavicular area (P < 0.05). Systemic macroanatomy revealed that the thumb-sized BAT in the posterior mediastinal descending para-aortic area (paBAT) had feeding vessels from the posterior intercostal arteries and veins and sympathetic/parasympathetic innervation from trunks of the sympathetic and vagus nerves, respectively. Immunohistochemical analysis indicated that the paBAT exhibited immunoreactivity for tyrosine hydroxylase and vesicular acetylcholine transporter located in the pericellular nervous fibers and intracellular UCP1. The brown adipose cells of paBAT showed age-dependent decreases in UCP1 expression (P < 0.05), accompanied by a significant increase in vacuole formation, indicating fat accumulation (P < 0.05), from 10 to 37 years of age (P < 0.01). CONCLUSIONS:paBAT may be one of the essential sites for clinical application in BAT study because of its visible anatomy with feeding vessels and sympathetic/parasympathetic innervation functionally affected by outer condition and senescence

Univariate multinomial logistic regression analysis of BAT morphology.

<p>The odds ratio and 95% confidence interval (95% CI) of sex and age were estimated according to the morphology of descending para-aortic BATs. The column uni/uni represents analysis of the unilocular type referring to the unilocular; multi/uni, multilocular type referring to the unilocular type; pauci/uni, the paucilocular type referring to the unilocular type; and multi/pauci, the multilocular type referring to the paucilocular type. Odds ratios (95% CI): associated <i>p</i>-values are shown in the univariate column, except the odds ratio of uni/uni, which is represented as 1.00. The outcome of univariate multinomial logistic analysis for each variable is shown in column <i>p</i>.</p><p>* <i>p</i>-values refer to the unilocular type of every variable as <0.05.</p><p>† <i>p</i>-values of the univariate multinomial logistic analysis of every variable were <0.05.</p><p>Univariate multinomial logistic regression analysis of BAT morphology.</p

Hierarchical clustering according to BAC cellularity.

<p>Summary of hierarchical clustering analysis of the immunohistochemical data of 21 UCP1-positive cases. The number and the word represent the individual case and each cellularity, respectively. The arrows show the range of the same cluster. Further, the branch length represents the similarity between results obtained in this system. UCP1-positive cases in the present study were classified into three groups according to the results: multi, the multilocular-dominant group; pauci, the paucilocular-dominant group; uni, the unilocular-dominant group. Cluster I comprised multi and pauci, Cluster II was equal to uni. %multilocular, percentage of area occupied with the multilocular cells; %paucilocular, percentage of area occupied with the paucilocular cells; %unilocular, percentage of area occupied with the unilocular cells. The score of the heat map in the lower right box represents the normalized distance among parameters.</p

Aging and BAT morphology.

<p>Inverted triangle and triangle symbols represent males and females, respectively. The solid, gray, and open symbols indicate the multilocular (multi), paucilocular (pauci), and unilocular (uni) types, respectively. (A) Scatter plot of UCP1-positive area (%) <i>vs</i>. age. (B) Scatter plot of vacuole area (%) <i>vs</i>. age. (C) Scatter plot of UCP1-positive area (%) <i>vs</i>. vacuole area (%). (D) Sigmoid plot of morphological proportion vs. age using logistic regression. The morphological proportion represents the proportion of occupation of each morphological type compared to the other types. The solid and gray curves indicate the morphological proportion of the multi and uni types, respectively. The left lower, middle, and right upper regions show the distribution of the multi, pauci, and uni types of BAT morphology. The fine and rough broken lines show the age cut-off values of 10 years for the multi and 37 years for the uni types, respectively.</p

Age and sex distribution in the anatomical examination.

<p>Using hematoxylin and eosin (HE) staining, we examined 78 autopsied tissue samples followed by immunohistochemical staining of 21 samples using a human anti-UCP1 antibody. The numerical data correspond to HE staining and the numbers in parentheses to UCP1 immunohistochemical staining. In the histochemical examination, the age deviations (mean ± SD) were 30.9 ± 26.3, 30.9 ± 27.0 and 30.9 ± 25.7 for all 78 cases, 45 males, and 33 females, respectively. In the immunohistochemical study, the age deviations (mean ± SD) were 30.0 ± 28.4, 18.3 ± 22.9, and 40.7 ± 29.7 for all 21 cases, 9 males, and 11 females, respectively.</p><p>Age and sex distribution in the anatomical examination.</p

Univariate logistic regression analysis of BAT morphology.

<p>The odds ratio, 95% confidence interval (95% CI) and associated p-values of sex and age were estimated according to the morphology of the descending para-aortic BATs. The column <i>Multilocular vs</i>. <i>others</i> represents analysis of the multilocular type referring to the other locular types; <i>Paucilocular vs</i>. <i>others</i>, of the paucilocular type referring to the other types; <i>Unilocular vs</i>. <i>others</i> of the unilocular type referring to the other types, respectively.</p><p>† <i>p</i>-values of the univariate logistic analysis of the variables were <0.001.</p><p>Univariate logistic regression analysis of BAT morphology.</p