The Mechanistic Links Between Proteasome Activity,Aging and Age-related Diseases

Damaged and misfolded proteins accumulate during the aging process, impairing cell function and tissue homeostasis. These perturbations to protein homeostasis (proteostasis) are hallmarks of age-related neurodegenerative disorders such as Alzheimer’s, Parkinson’s or Huntington’s disease. Damaged proteins are degraded by cellular clearance mechanisms such as the proteasome, a key component of the proteostasis network. Proteasome activity declines during aging, and proteasomal dysfunction is associated with late-onset disorders. Modulation of proteasome activity extends lifespan and protects organisms from symptoms associated with proteostasis disorders. Here we review the links between proteasome activity, aging and neurodegeneration. Additionally, strategies to modulate proteasome activity and delay the onset of diseases associated to proteasomal dysfunction are discussed herein.     

Genetic Variants in Diseases of the Extrapyramidal System

Knowledge on the genetics of movement disorders has advanced significantly in recent years. It is now recognized that disorders of the basal ganglia have genetic basis and it is suggested that molecular genetic data will provide clues to the pathophysiology of normal and abnormal motor control. Progress in molecular genetic studies, leading to the detection of genetic mutations and loci, has contributed to the understanding of mechanisms of neurodegeneration and has helped clarify the pathogenesis of some neurodegenerative diseases. Molecular studies have also found application in the diagnosis of neurodegenerative diseases, increasing the range of genetic counseling and enabling a more accurate diagno-sis. It seems that understanding pathogenic processes and the significant role of genetics has led to many experiments that may in the future will result in more effective treatment of such diseases as Parkinson’s or Huntington’s. Currently used molecular diagnostics based on DNA analysis can identify 9 neurodegenerative diseases, including spinal cerebellar ataxia inherited in an autosomal dominant manner, dentate-rubro-pallido-luysian atrophy, Friedreich’s disease, ataxia with ocu-lomotorapraxia, Huntington''s disease, dystonia type 1, Wilson’s disease, and some cases of Parkinson''s disease.     

Parkinson’s disease and enhanced inflammatory response

Parkinson’s disease (PD) is the first and second most prevalent motor and neurodegenerative disease, respectively. The clinical symptoms of PD result from a loss of midbrain dopaminergic (DA) neurons. However, the molecular cause of DA neuron loss remains elusive. Mounting evidence implicates enhanced inflammatory response in the development and progression of PD pathology. This review examines current research connecting PD and inflammatory response.     

Pharmacogenetics of Parkinson’s Disease – Through Mechanisms of Drug Actions

In the last years due to development of molecular methods a substantial progress in understanding of geneticassociations with drug effects in many clinical disciplines has been observed. The efforts to define the role of genetic polymorphismsin optimizing pharmacotherapy of Parkinson’s disease (PD) were also undertaken. So far, some promisinggenetic loci for PD treatment were determined. In the review pharmacogenetic aspects of levodopa, dopamine agonistsand COMT inhibitors are discussed.     

Donepezil attenuates high glucose-accelerated senescence in human umbilical vein endothelial cells through SIRT1 activation

Cellular senescence of endothelial cells is a damage and stress response which induces pro-inflammatory, pro-atherosclerotic, and pro-thrombotic phenotypes. Donepezil is a drug used for the treatment of mild to moderate dementia of the Alzheimer’s disease (AD). The aim of the present study was to investigate the attenuation of endothelial cell senescence by donepezil and to explore the mechanisms underlying the anti-aging effects of donepezil. Our results indicated that high glucose (HG) markedly decreased cell viability of human umbilical vein endothelial cells (HUVECs), and this phenomenon was reversed by treatment with donepezil. Importantly, our results displayed that the frequency of senescent (SA-ß-gal-positive) cells and the expression level of senescence genes (PAI-1 and p21) were significantly higher in the HG group compared with the normal glucose (NG) group, and these changes were blocked by treatment with donepezil. Also, our results showed that donepezil inhibits the generation of reactive oxygen species (ROS), which promotes cellular senescence. Pretreatment with nicotinamide (NAM), a sirtuin 1 (SIRT1) inhibitor, inhibited the reduction in senescence associated with donepezil. Indeed, our results indicated that donepezil increased the SIRT1 enzyme activity. Therefore, these results show that donepezil delays cellular senescence that is promoted under HG condition via activation of SIRT1.     

Study of EEG microstates in Parkinson’s disease: a potential biomarker?

The spontaneous activity of the brain is dynamic even at rest and the deviation from this normal pattern of dynamics can lead to different pathological states. EEG microstate analysis of resting-state neuronal activity in Parkinson’s disease (PD) could provide insight into altered brain dynamics of patients exhibiting dementia. Resting-state EEG microstate maps were derived from 128 channel EEG data in 20 PD without dementia (PDND), 18 PD with dementia (PDD) and 20 Healthy controls (CON) using Cartool and sLORETA softwares. Microstate map parameters including global explained variance, mean duration, frequency of occurrence (TF) and time coverage were compared statistically among the groups. Eight maps that explained 72% of the topographic variance were identified and only three maps differed significantly across the groups. TF of Map1 was lower in both PDND and PDD (p < 0.001) and that of Map3 (p = 0.02) in PDND compared to control. Cortical sources showed higher activation in precuneus, cuneus and superior parietal lobe (Threshold: Log-F = 1.74, p < 0.05) with maximum activity in the precuneus region (MNI co-ordinates: − 25, − 75, − 40; Log-F = 1.9) in PDND compared to control only for Map1. Lower TF of Map1 (prototypical microstate D) may potentially serve as a biomarker for PD with or without dementia whereas higher activation of precuneus, cuneus and superior parietal lobe at resting-state could favour signal processing, lack of which could be associated with dementia in Parkinson’s disorder.     

Recognizing the cooperative and independent mitochondrial functions of Parkin and PINK1

Comment on: Johnson BN, et al. Proc Natl Acad Sci USA 2012; 109:6283-8.     

Perianal Crohn’s disease and hidradenitis suppurativa: a possible common immunological scenario

Background

Crohn’s disease (CD) and Hidradenitis suppurativa (HS) are both chronic inflammatory diseases. The pathogenesis of these diseases is multifactorial, due to the interaction of genetic and environmental factors leading to a deregulated local immune response where T lymphocytes play a major role. To the best of our knowledge, no previous study has clarified whether the pathogenetic mechanism of perianal CD and HS is the same. We therefore analyzed the cellular expression pattern and the cytokine repertoire in three patients suffering from both perianal CD and HS.

Methods

We evaluated three patients affected by concurrent HS and CD with fistulizing perianal disease. Surgical specimens have been fixed and embedded in paraffin prior to sectioning for histological examination. Inflammatory tissue curettages have been recovered during intervention from perianal fistulas and HS lesions in order to analyze the phenotypic and functional characteristics of infiltrating T cells. In particular we evaluated T cells, by flow cytometry, for cytokine production profile and expression of surface markers. Moreover, analysis of the T cell repertoire was performed by means of spectratyping, in only one patient.

Results

A higher frequency of CD4+ CD161+ T lymphocytes has been detected in CD fistulas and in HS lesions than in peripheral blood (PB) samples. In the patient in whom we derived enough cells from the three sources, we found higher frequency of CD4+ IL-17- producing cells in HS lesion and fistula lesion compared to PB. It is noteworthy that the same clonotypes were expanded in this patient in T cells derived from both HS lesion and fistula lesion.

Conclusion

The presence of numerous CD4+ CD161+ lymphocytes in fistula and HS lesion curettages suggests that these cells may play a pathogenic role, and candidates CD161 as a possible biological target for medical treatment.     

Functional and Structural Effects of Amyloid-β Aggregate on Xenopus laevis Oocytes

Xenopus laevis oocytes exposed to amyloid-β aggregate generated oscillatory electric activity (blips) that was recorded by two-microelectrode voltage-clamp. The cells exhibited a series of “spontaneous” blips ranging in amplitude from 3.8 ± 0.9 nA at the beginning of the recordings to 6.8 ± 1.7 nA after 15 min of exposure to 1 μM aggregate. These blips were similar in amplitude to those induced by the channel-forming antimicrobial agents amphotericin B (7.8 ± 1.2 nA) and gramicidin (6.3 ± 1.1 nA). The amyloid aggregate-induced currents were abolished when extracellular Ca²⁺ was removed from the bathing solution, suggesting a central role for this cation in generating the spontaneous electric activity. The amyloid aggregate also affected the Ca²⁺-dependent Cl⁻ currents of oocytes, as shown by increased amplitude of the transient-outward chloride current (T_out) and the serum-activated, oscillatory Cl⁻ currents. Electron microcopy revealed that amyloid aggregate induced the dissociation of the follicular cells that surround the oocyte, thus leading to a failure in the electro-chemical communication between these cells. This was also evidenced by the suppression of the oscillatory Ca²⁺-dependent ATP-currents, which require proper coupling between oocytes and the follicular cell layer. These observations, made using the X. laevis oocytes as a versatile experimental model, may help to understand the effects of amyloid aggregate on cellular communication.