Original Article

The present paper deals with an investigation on the changes appearing in the mucous membrane of the nose (physiologic atrophy) in normal persons of different age groups, as contrasted with a wasting of the mucous mambrane of the nose in cases of atrophic rhinitis. The investigation has been performed for the purpose of contributing to the studies of the pathology of atrophic rhinitis. 1. Pathologic changes of a considerable degree were. observed in the epithelium in quite a large section of infants and children where it had been considered normal as a results of macroscopic examinations. 2. Metaplasia of the epithelial cells developing in the mucous membrane in the forepart of the respiratory region seems to occur as a result of the stimulus applied from without. The phenomenon was marked in the front and along the lower edge of the inferior turbinal, showing a tendency to increase in magnitude as the age advance. It did not, however, spread over a wide area, nor was there any marked development of cornification. An increase in mucus secretion, as well as in the number of goblet cells, was noticed in the epithelium as the age advance. Mucous degeneration gradually set in at the end of forties, becoming marked in the sixties. 4. In the basal membrane, the hyaline layer, which is its secondary form, grew in size with age, and a substance which stains with Hale\u27s stain was detected in it. This substance seems to have an important share in the mucus secreting function of the epithelium. 5. It seems that the epithelium of the mucous membrane of the upper respiratory tract continues to function even in considerably advanced ages. 6. The lymphoid tissue situated underneath the epithelium attained the largest quantity in persons about 20 years old; it began to diminish and grow less thick in persons over 40. The presence of the elastic fiber was noticed in the subepithelial layer in all age groups, though the number of persons with this phenomenon was small.7. The glands wers under-developed in children of about 10; they grew rapidly after that age until about 40 when they began to show a tendency to atrophy. 8. It seems that the periglandular lymphocytes, which infiltrate without bringing about the disintegration of the glands, take charge of the metabolism of the glands. A large number of them were found in infancy but they showed a marked decrease in number in persons over about 40. It would seem that, in highly advanced ages, non-inflammatory disintegration of the glands could possibly occur as a result of the infiltration of the lymphoid tissue. 9. The formation of the oncocyte, an unusual cell of the epithelium of the gland which characterizes the old age, was noticed in 7 cases. 10. The blood vessels manifested changes of a high degree in persons of advanced ages: they revealed evidences of functional disturbance of a high degree when stained by the stains of H. E, Weigert, PAS and Hale. This would show the measure of the influence that has been exerted on the function of the mucous membrane. 11. Corpora cavernosa was under-developed in infancy but became well-developed in persons of about 20; a decrease in the number of bodies and a diminution in size of the inner lumen became marked in persons over 40, becoming more marked in persons over 50

Genotype frequencies and association results for the tests performed in the Dutch series.

<p>Genotype frequencies and association results for the tests performed in the Dutch series.</p

Unbiased hierarchical clustering of all gene expression profiles of iLBD, PD and control donors.

<p>Red is control, blue is iLBD and green is PD donor. The two main clusters are formed by 1) controls and iLBD and 2) PD and iLBD, indicating that the expression of iLBD is intermediate between control and PD. Seven samples clustered separately from the two main clusters. There were no technical reasons however, to exclude these donors from the analysis.</p

Alterations in elements of mTOR, EIF2 and EIF4 signaling pathways in Braak alpha-synuclein 1 and 2 compared to controls.

<p>Image generated using Ingenuity pathway analysis (IPA).</p

Alterations in expression levels of genes involved in endocytosis in the early Braak alpha-synuclein stages 1 and 2 and PD, compared to controls

<p>Alterations in expression levels of genes involved in endocytosis in the early Braak alpha-synuclein stages 1 and 2 and PD, compared to controls</p

Alterations in expression levels of alpha-synuclein and known interactors of alpha-synuclein in Braak 1–2 and PD compared to controls.

<p>Alterations in expression levels of alpha-synuclein and known interactors of alpha-synuclein in Braak 1–2 and PD compared to controls.</p

Schematic overview of molecular processes altered during disease progression in the SN of PD, identified using transcriptome analysis.

<p>In Braak alpha-synuclein 1 and 2, minimal cell loss is observed along with decreased endocytosis and anterograde trafficking, and increased immune response and microglial activation. In addition, we observed down regulation of mRNA levels of the upstream regulators in mTOR pathway. In Braak alpha-synuclein 3 and 4, a steep decline in cell loss and increase in alpha-synuclein pathology is observed together disturbed regulation of protein production and apoptosis of the nigral dopaminergic cells. In Braak alpha-synuclein 5 and 6 compared to controls, severe cell loss and alpha-synuclein aggregation is observed [<a href="http://www.plosone.org/article/info:doi/10.1371/journal.pone.0128651#pone.0128651.ref041" target="_blank">41</a>]. At this advanced stage, alterations in pathways related to dopaminergic signaling and immune response are still observed.</p

Evidence for Immune Response, Axonal Dysfunction and Reduced Endocytosis in the Substantia Nigra in Early Stage Parkinson’s Disease

<div><p>Subjects with incidental Lewy body disease (iLBD) may represent the premotor stage of Parkinson’s disease (PD). To elucidate molecular mechanisms underlying neuronal dysfunction and alpha-synuclein pathology in the premotor phase of PD, we investigated the transcriptome of the substantia nigra (SN) of well-characterized iLBD, PD donors and age-matched controls with Braak alpha-synuclein stage ranging from 0–6. In Braak alpha-synuclein stages 1 and 2, we observed deregulation of pathways linked to axonal degeneration, immune response and endocytosis, including axonal guidance signaling, mTOR signaling, EIF2 signaling and clathrin-mediated endocytosis in the SN. In Braak stages 3 and 4, we observed deregulation of pathways involved in protein translation and cell survival, including mTOR and EIF2 signaling. In Braak stages 5 and 6, we observed deregulation of dopaminergic signaling, axonal guidance signaling and thrombin signaling. Throughout the progression of PD pathology, we observed a deregulation of mTOR, EIF2 and regulation of eIF4 and p70S6K signaling in the SN. Our results indicate that molecular mechanisms related to axonal dysfunction, endocytosis and immune response are an early event in PD pathology, whereas mTOR and EIF2 signaling are impaired throughout disease progression. These pathways may hold the key to altering the disease progression in PD.</p></div

Molecular pathways associated with the up- or down-regulated genes in end-stage PD (Braak 5–6) versus controls in our study, compared to other transcriptome studies.

<p>* novel pathways in the SN in PD compared to control</p><p>** BH-FDR<0.05 displayed;</p><p>***Fisher p-value<0.05 displayed</p><p>Molecular pathways associated with the up- or down-regulated genes in end-stage PD (Braak 5–6) versus controls in our study, compared to other transcriptome studies.</p

Trehalose induces autophagy and activates autophagic flux in CHIP-mutant fibroblasts.

<p>The cells were treated for 24 h with o without trehalose 50 mM in the presence or absence of 10 µM chloroquine (CQ), a lysosomotropic agent widely used to block lysosomal degradation. <b>A</b>) Fluorescence microscopy images showing autophagosome marker LC-3 (green), lysosomal marker Lamp-2A (red) and LC3-LAMP-2A colocalization (yellow). (Scale bar  = 20 µm). <b>B</b>) Integrated optical density (IOD) quantification of LC3 expression. <b>C</b>) The lysosomal degradation was measured by IOD quantification of colocalization LC-3-LAMP-2A (yellow). <b>D</b>) Western blot showing LC3-II accumulation. Data of the control and CHIP-mutant groups were analyzed independently, no inter-group statistical analysis was performed. Data are expressed as the mean ± SEM. In 7B and 7C values are the mean ± S.E.M. of six independent coverslips (each value represents the mean of 20 field for coverslip). Three individuals with the mean of 2 independent coverslips (n = 3) in the control group and in the CHIP-mutant group 6 independent coverslips of the only patient (pseudo-replicates, n = 6). In 7D values represents the mean of 2 independent dishes of cells of 2 controls (n = 2) and for the CHIP-mutant group one patient with four independent dishes (pseudo-replicates, n = 4). Statistical analysis was performed by Student's t-test. *p<0.05, **p<0.01, ***p<0.001 <i>vs</i> solvents without chloroquine; δδp<0.01, δδδp<0.001 trehalose -CQ <i>vs</i> trehalose + CQ treated cultures.</p