A systematic review of the biological processes involved in deep-brain stimulation for parkinson’s disease: A focus on the potential disease-modifying effects

Deep-Brain Stimulation (DBS) is an important treatment option for the management of Parkinson’s disease (PD) and is a common symptomatic treatment. However, an increasing number of studies have examined the biological processes to assess if DBS can also modify the natural history of PD by acting on its pathophysiological mechanisms. Relevant literature published up to November 2020 was systematically searched on databases such as PubMed, ISI Web of Knowledge, Academic Search Index, and Science Citation Index. The following predefined inclusion criteria were applied to the full-text versions of the selected articles: I) recruiting and monitoring of PD subjects that were previously treated with DBS and ii) investigating the electrophysiological, biochemical, epigenetic, or neuroimaging effects of DBS. Studies focusing exclusively on motor and clinical changes were excluded. Reviews, case reports, studies on animal models, and computational studies were also not considered. Out of 2,960 records screened, 43 studies met the inclusion criteria. Only three studies described a potential disease-modifying effect of DBS. However, a wide heterogeneity was observed in the investigated biomarkers, and the design and methodological issues of several studies limited their ability to find potential disease-modifying features. Specifically, 60.4% of the trials followed-up subjects for no more than 1 year from the surgical intervention, and 67.4% observed patients with PD only once after DBS. Moreover, 64.2% of the studies enrolled late-stage PD patients. Most of the studies (88.4%) reported that DBS only had a symptomatic effect, with several of them showing some limitations in the study design and recruitment of patients. Further studies using shared biomarkers are encouraged to assess if and how DBS might affect the progression of PD. Based on the existing preclinical literature, prospective clinical trials examining the course of PD in early-stage patients are needed

The long non-coding RNAs in neurodegenerative diseases : novel mechanisms of pathogenesis

Background: Long-non-coding RNAs (lncRNAs), RNA molecules longer than 200 nucleotides, have been involved in several biological processes and in a growing number of diseases, controlling gene transcription, pre-mRNA processing, the transport of mature mRNAs to specific cellular compartments, the regulation of mRNA stability, protein translation and turnover. The fundamental role of lncRNAs in central nervous system (CNS) is becoming increasingly evident. LncRNAs are abundantly expressed in mammalian CNS in a specific spatio-temporal manner allowing a quick response to environmental/molecular changes. Methods: This article reviews the biology and mechanisms of action of lncRNAs underlying their potential role in CNS and in some neurodegenerative diseases. Results: an increasing number of studies report on lncRNAs involvement in different molecular mechanisms of gene expression modulation in CNS, from neural stem cell differentiation mainly by chromatin remodeling, to control of neuronal activities. More recently, lncRNAs have been implicated in neurodegenerative diseases, including Alzheimer\u2019s Disease, where the role of BACE1-AS lncRNA has been widely defined. BACE1-AS levels are up-regulated in AD brains where BACE1-AS acts by stabilizing BACE1 mRNA thereby increasing BACE1 protein content and A\u3b242 formation. In Frontotemporal dementia and Amyotrophic lateral sclerosis the lncRNAs NEAT1_2 and MALAT1 co-localize at nuclear paraspeckles with TDP-43 and FUS proteins and their binding to TDP-43 is markedly increased in affected brains. In Parkinson\u2019s Disease the lncRNA UCHL1-AS1 acts by directly promoting translation of UCHL1 protein leading to perturbation of the ubiquitin-proteasome system. Different lncRNAs, such as HTT-AS, BDNF-AS and HAR1, were found to be dysregulated in their expression also in Huntington\u2019s Disease. In Fragile X syndrome (FXS) and Fragile X tremor/ataxia syndrome (FXTAS) patients, the presence of CGG repeats expansion alters the expression of the lncRNAs FMR1-AS1 and FMR6. Interestingly, they are expressed in peripheral blood leukocytes, suggesting these lncRNAs may represent biomarkers for FXS/FXTAS early detection and therapy. Finally, the identification of the antisense RNAs SCAANT1-AS and ATXN8OS in spinocerebellar ataxia 7 and 8, respectively, suggests that very different mechanisms of action driven by lncRNAs may trigger neurodegeneration in these disorders. The emerging role of lncRNAs in neurodegenerative diseases suggests that their dysregulation could trigger neuronal death via still unexplored RNA-based regulatory mechanisms which deserve further investigation. The evaluation of their diagnostic significance and therapeutic potential could also address the setting up of novel treatments in diseases where no cure is available to date

A Systematic Review of the Biological Processes Involved in Deep-Brain Stimulation for Parkinson's disease: A Focus on the Potential Disease-Modifying Effects

Deep-Brain Stimulation (DBS) is an important treatment option for the management of Parkinson's disease (PD) and is a common symptomatic treatment. However, an increasing number of studies have examined the biological processes to assess if DBS can also modify the natural history of PD by acting on its pathophysiological mechanisms. Relevant literature published up to November 2020 was systematically searched on databases such as PubMed, ISI Web of Knowledge, Academic Search Index, and Science Citation Index. The following predefined inclusion criteria were applied to the full-text versions of the selected articles: i) recruiting and monitoring of PD subjects that were previously treated with DBS and ii) investigating the electrophysiological, biochemical, epigenetic, or neuroimaging effects of DBS. Studies focusing exclusively on motor and clinical changes were excluded. Reviews, case reports, studies on animal models, and computational studies were also not considered. Out of 2,960 records screened, 43 studies met the inclusion criteria. Only three studies described a potential disease-modifying effect of DBS. However, a wide heterogeneity was observed in the investigated biomarkers, and the design and methodological issues of several studies limited their ability to find potential disease-modifying features. Specifically, 60.4% of the trials followed-up subjects for no more than 1 year from the surgical intervention, and 67.4% observed patients with PD only once after DBS. Moreover, 64.2% of the studies enrolled late-stage PD patients. Most of the studies (88.4%) reported that DBS only had a symptomatic effect, with several of them showing some limitations in the study design and recruitment of patients. Further studies using shared biomarkers are encouraged to assess if and how DBS might affect the progression of PD. Based on the existing preclinical literature, prospective clinical trials examining the course of PD in early-stage patients are needed

Long non-coding RNA and alternative splicing modulations in Parkinson's leukocytes identified by RNA sequencing.

The continuously prolonged human lifespan is accompanied by increase in neurodegenerative diseases incidence, calling for the development of inexpensive blood-based diagnostics. Analyzing blood cell transcripts by RNA-Seq is a robust means to identify novel biomarkers that rapidly becomes a commonplace. However, there is lack of tools to discover novel exons, junctions and splicing events and to precisely and sensitively assess differential splicing through RNA-Seq data analysis and across RNA-Seq platforms. Here, we present a new and comprehensive computational workflow for whole-transcriptome RNA-Seq analysis, using an updated version of the software AltAnalyze, to identify both known and novel high-confidence alternative splicing events, and to integrate them with both protein-domains and microRNA binding annotations. We applied the novel workflow on RNA-Seq data from Parkinson's disease (PD) patients' leukocytes pre- and post- Deep Brain Stimulation (DBS) treatment and compared to healthy controls. Disease-mediated changes included decreased usage of alternative promoters and N-termini, 5'-end variations and mutually-exclusive exons. The PD regulated FUS and HNRNP A/B included prion-like domains regulated regions. We also present here a workflow to identify and analyze long non-coding RNAs (lncRNAs) via RNA-Seq data. We identified reduced lncRNA expression and selective PD-induced changes in 13 of over 6,000 detected leukocyte lncRNAs, four of which were inversely altered post-DBS. These included the U1 spliceosomal lncRNA and RP11-462G22.1, each entailing sequence complementarity to numerous microRNAs. Analysis of RNA-Seq from PD and unaffected controls brains revealed over 7,000 brain-expressed lncRNAs, of which 3,495 were co-expressed in the leukocytes including U1, which showed both leukocyte and brain increases. Furthermore, qRT-PCR validations confirmed these co-increases in PD leukocytes and two brain regions, the amygdala and substantia-nigra, compared to controls. This novel workflow allows deep multi-level inspection of RNA-Seq datasets and provides a comprehensive new resource for understanding disease transcriptome modifications in PD and other neurodegenerative diseases

Cholinergic Surveillance over Hippocampal RNA Metabolism and Alzheimer's-Like Pathology

The relationship between long-term cholinergic dysfunction and risk of developing dementia is poorly understood. Here we used mice with deletion of the vesicular acetylcholine transporter (VAChT) in the forebrain to model cholinergic abnormalities observed in dementia. Whole-genome RNA sequencing of hippocampal samples revealed that cholinergic failure causes changes in RNA metabolism. Remarkably, key transcripts related to Alzheimer's disease are affected. BACE1, for instance, shows abnormal splicing caused by decreased expression of the splicing regulator hnRNPA2/B1. Resulting BACE1 overexpression leads to increased APP processing and accumulation of soluble Aβ1-42. This is accompanied by age-related increases in GSK3 activation, tau hyperphosphorylation, caspase-3 activation, decreased synaptic markers, increased neuronal death, and deteriorating cognition. Pharmacological inhibition of GSK3 hyperactivation reversed deficits in synaptic markers and tau hyperphosphorylation induced by cholinergic dysfunction, indicating a key role for GSK3 in some of these pathological changes. Interestingly, in human brains there was a high correlation between decreased levels of VAChT and hnRNPA2/B1 levels with increased tau hyperphosphorylation. These results suggest that changes in RNA processing caused by cholinergic loss can facilitate Alzheimer's-like pathology in mice, providing a mechanism by which decreased cholinergic tone may increase risk of dementia

The relationship of microRNAs to clinical features of Huntington's and Parkinson's disease

MicroRNAs (miRNAs) represent a major system of post-transcriptional regulation, by either preventing translational initiation or by targeting messenger RNA transcripts for storage or degradation. miRNA deregulation has been reported in neurodegenerative disorders, such as Huntington’s disease (HD) and Parkinson’s disease (PD), which may impact gene expression and modify disease progression and/or severity. To assess the relationship of miRNA levels to HD, small RNA sequence analysis was performed for 26 HD and 36 non-disease control samples derived from human prefrontal cortex. 75 miRNAs were differentially expressed in HD brain as compared to controls at genome-wide significance (FDR q<0.05). Among HD brains, nine miRNAs were significantly associated with the extent of neuropathological involvement in the striatum and three of these significantly related to a continuous measure of striatal involvement, after statistical adjustment for the contribution of HD gene length. Five miRNAs were identified as having a significant, inverse relationship to age of motor onset, in particular, miR-10b-5p, the mostly strongly over-expressed miRNA in HD cases. Although prefrontal cortex was the source of tissue profiled in these studies, the relationship of miR-10b-5p levels to striatal involvement in the disease was independent of cortical involvement. In blood plasma from 26 HD, 4 asymptomatic HD gene carriers and 8 controls, miR-10b-5p levels were significantly elevated in HD as compared to non-diseased and preclinical HD subjects, demonstrating that miRNA alterations associated with diseased brain may be detected peripherally. Using small RNA sequence analysis for 29 PD brains, 125 miRNAs were identified as differentially expressed at genome-wide significance (FDR q<0.05) in PD versus controls. A set of 29 miRNAs accurately classified PD from non-diseased brain (93.9% specificity, 96.6% sensitivity, 4.8% absolute error). In contrast to HD, among PD cases, miR-10b-5p was significantly decreased and had a significant, positive association to onset age independent of age at death. These studies provide a detailed miRNA profile for HD and PD brain, identify miRNAs associated with disease pathology and suggest miRNA changes observed in brain can be detected in blood. Together, these findings support the potential of miRNA biomarkers for the diagnosis and assessment of progression for neurodegenerative diseases

Cholinergic Mechanisms Regulating Cognitive Function and RNA Metabolism

Acetylcholine (ACh) is one of the main neuromodulators in the mammalian central nervous system (CNS). This chemical messenger has been implicated in the underlying physiology of many distinct cognitive functions. However, the exact role that ACh plays in regulating information processing in the brain is still not fully understood. The vesicular acetylcholine transporter (VAChT) is required for the storage of ACh into synaptic vesicles, and therefore it presents a means to modulate release. Diminished VAChT levels cause a decrease in cholinergic tone, whereas increased VAChT expression has been shown to augment ACh release. Previously published data have shown that elimination of VAChT in the basal forebrain in genetically-modified mice impairs learning and memory. For our studies we have used different mouse lines in which the expression of the VAChT gene is changed, both increased and decreased. We are therefore able to study the consequences of altered cholinergic tone in vivo. Our hypothesis is that changes in cholinergic tone produce specific molecular signatures in target brain areas that underlie alterations in cognitive function. Our studies aimed to elucidate the behavioural and molecular consequences of cholinergic dysfunction. Behavioral testing included classical learning and memory tests as well as sophisticated tasks using novel touch screens chambers to measure attention, learning and memory as well as cognitive flexibility. At the molecular level, the goal was to examine how long-term changes in cholinergic tone impact mechanisms regulating synaptic plasticity and neuronal health. Finally, by aging mouse models of cholinergic dysfunction we were able to elucidate the role that cholinergic tone plays in the classical pathological hallmarks of neurodegenerative disorders. Ultimately, by establishing the molecular signature of increased and decreased cholinergic tone in targeted brain regions (cortex and hippocampus) it may become possible to find novel targets for therapeutic interventions to improve cognitive deficits due to altered cholinergic tone