Selective neuronal vulnerability in Parkinson disease

Nature reviews. Neuroscience, Год журнала: 2017, Номер 18(2), С. 101 - 113

Опубликована: Янв. 20, 2017

Язык: Английский

---

On Cell Loss and Selective Vulnerability of Neuronal Populations in Parkinson's Disease

Frontiers in Neurology, Год журнала: 2018, Номер 9

Опубликована: Июнь 19, 2018

Significant advances have been made uncovering the factors that render neurons vulnerable in Parkinson's disease (PD). However, critical pathogenic events leading to cell loss remain poorly understood, complicating development of disease-modifying interventions. Given cardinal motor symptoms and pathology PD involve dopamine (DA) substantia nigra pars compacta (SNc), a majority work field has focused on this specific neuronal population. however, is not DA exclusively: pathology, most notably form Lewy bodies neurites, reported multiple regions central peripheral nervous system, including for example locus coeruleus, dorsal raphe nucleus vagus. Cell and/or terminal these additional nuclei likely contribute some other and, non-motor features. exactly what show actual, well-documented, presently unclear. In review we will first examine strength evidence describing idiopathic PD, as well order which occurs. Secondly, discuss neurochemical, morphological physiological characteristics SNc vulnerable, being shared across PD-affected populations. Some insights raised by focusing underpinnings selective vulnerability might be helpful facilitate new strategies improve animal models disease.

Язык: Английский

---

Determinants of dopaminergic neuron loss in Parkinson's disease

FEBS Journal, Год журнала: 2018, Номер 285(19), С. 3657 - 3668

Опубликована: Июль 20, 2018

The cardinal motor symptoms of Parkinson's disease (PD) are caused by the death dopaminergic neurons in substantia nigra pars compacta (SNc). Alpha-synuclein (aSYN) pathology and mitochondrial dysfunction have been implicated PD pathogenesis, but until recently it was unclear why SNc should be particularly vulnerable to these two types insult. In this brief review, evidence that an anatomical, physiological, biochemical phenotype predisposes them synuclein is summarized. recognition certain traits may predispose PD-linked creates translational opportunities for slowing or stopping progression.

Язык: Английский

---

Targeting AMPK Signaling as a Neuroprotective Strategy in Parkinson’s Disease

Journal of Parkinson s Disease, Год журнала: 2018, Номер 8(2), С. 161 - 181

Опубликована: Март 27, 2018

Parkinson's disease (PD) is the second most common neurodegenerative disorder.It characterized by accumulation of intracellular ␣-synuclein aggregates and degeneration nigrostriatal dopaminergic neurons.While no treatment strategy has been proven to slow or halt progression disease, there mounting evidence from preclinical PD models that activation 5 -AMP-activated protein kinase (AMPK) may have broad neuroprotective effects.Numerous dietary supplements pharmaceuticals (e.g., metformin) increase AMPK activity are available for use in humans, but clinical studies their effects patients limited.AMPK an evolutionarily conserved serine/threonine activated falling energy levels functions restore cellular balance.However, response certain stressors, exacerbate neuronal atrophy cell death.This review describes regulation AMPK, evaluates controversies field, assesses potential targeting signaling as a PD.

Язык: Английский

---

A Parkinson’s disease CircRNAs Resource reveals a link between circSLC8A1 and oxidative stress

EMBO Molecular Medicine, Год журнала: 2020, Номер 12(11)

Опубликована: Ноя. 6, 2020

Язык: Английский

---

Physiological Roles and Therapeutic Potential of Ca2+ Activated Potassium Channels in the Nervous System

Frontiers in Molecular Neuroscience, Год журнала: 2018, Номер 11

Опубликована: Июль 30, 2018

Within the potassium ion channel family, calcium activated (KCa) channels are unique in their ability to couple intracellular Ca2+ signals membrane potential variations. KCa diversely distributed throughout central nervous system and play fundamental roles ranging from regulating neuronal excitability controlling neurotransmitter release. The physiological versatility of is enhanced by alternative splicing co-assembly with auxiliary subunits, leading differences distribution, subunit composition pharmacological profiles. Thus, understanding specific channels' mechanisms function challenging. Based on single conductance, divided into three subtypes: small (SK, 4-14 pS), intermediate (IK, 32-39 pS) big (BK, 200-300 channels. This review describes biophysical characteristics these channels, as well pathological implications. In addition, we also discuss current strategies challenges target for treatment various neurological psychiatric disorders.

Язык: Английский

---

A Parkinson's disease Circ RNA s Resource reveals a link between circ SLC 8A1 and oxidative stress

EMBO Molecular Medicine, Год журнала: 2020, Номер 12(9)

Опубликована: Июль 26, 2020

Resource26 July 2020Open Access Transparent process A Parkinson's disease CircRNAs Resource reveals a link between circSLC8A1 and oxidative stress Mor Hanan Department of Biological Chemistry, The Institute Life Sciences, Hebrew University Jerusalem, Israel Edmond Lily Safra Center for Brain Search more papers by this author Alon Simchovitz Nadav Yayon Shani Vaknine Roni Cohen-Fultheim Mina Everard Goodman Faculty Bar-Ilan University, Ramat Gan, Miriam Karmon Nimrod Madrer Talia Rohrlich Genetics, Moria Maman Estelle R Bennett David S Greenberg Eran Meshorer Erez Y Levanon orcid.org/0000-0002-3641-4198 Hermona Soreq Corresponding Author [email protected] orcid.org/0000-0002-0955-526X Sebastian Kadener orcid.org/0000-0003-0080-5987 Biology Department, Brandeis Waltham, MA, USA Information Hanan1,2, Simchovitz1,2, Yayon1,2, Vaknine1,2, Cohen-Fultheim3, Karmon3, Madrer1,2, Rohrlich2,4, Maman2,4, Bennett1,2, Greenberg1,2, Meshorer2,4, Levanon3, *,1,2 *,1,5 1Department 2The 3Mina 4Department 5Biology *Corresponding author. Tel: +972 548820629; E-mail: EMBO Mol Med (2020)12:e11942https://doi.org/10.15252/emmm.201911942 Correction(s) article stress06 November 2020 PDFDownload PDF text main figures. Peer ReviewDownload summary the editorial decision including letters, reviewer comments responses to feedback. ToolsAdd favoritesDownload CitationsTrack CitationsPermissions ShareFacebookTwitterLinked InMendeleyWechatReddit Figures & Info Abstract Circular RNAs (circRNAs) are brain-abundant mostly unknown functions. To seek their roles in (PD), we generated an RNA sequencing resource several brain region tissues from dozens PD control donors. In healthy substantia nigra (SN), circRNAs accumulate age-dependent manner, but SN correlation is lost total number reduced. contrast, levels increased other studied regions patients. We also found increase individuals. CircSLC8A1 carries 7 binding sites miR-128 strongly bound microRNA effector protein Ago2. Indeed, targets individuals, suggesting that regulates function and/or activity. cultured cells exposed stress-inducing agent paraquat were decreased treated with neuroprotective antioxidant regulator drug Simvastatin. Together, our work links stress-related Parkinsonism suggests further exploration its molecular PD. Synopsis human brains, circRNA specific inversely correlate editing. reduced accumulation age lost. increases oxidation, Ago2 sponges miR128 targets, modulating neuronal survival aging. CircRNA be region-specific editing Alu repeats. Disease (PD) SN, individuals Paraquat. paper explained Problem leading neurodegenerative movement disorder; however, mechanisms underlying cellular degeneration brains remain poorly understood. recently discovered class expression patterns diseased largely unknown. Results used very deep explore three different patients, (SN) where dopaminergic neurons die brain, amygdala which responds stressful situations at large temporal gyrus harboring routes nuclei cortex. correlated Also, identified not focused experiments on CircSLC8A1, originates Ca2+ regulating SLC8A1 gene. Notably, one microRNA, miR-128, Correspondingly, activity miR-128. Impact Our findings establish expressed reveal previously expression, pathology, call exploring implications addressing initiation processes. Introduction second most common disorder, affecting 1–2% population over 65 (Farrer, 2006; Farrer et al, 2006). characterized progressive loss attributed multi-leveled elusive complex interactions genetic susceptibilities, male sex, environmental toxins, mitochondrial dysfunction, imbalanced signaling processes Consequent depletion nigrostriatal pathway striatal dopamine then lead prominent motor symptoms bradykinesia, hypokinesia, rigidity, resting tremor, postural stability. risk factors include exposure herbicides, pesticides, metal-derived substances (Collier 2011). major hallmark intracellular deposits (named Lewy bodies) primarily composed precipitates alpha-synuclein (SNCA) protein. Much knowledge genes pathways involved derives studies inherited forms disease. Those have been associated mutations (SNCA), synaptic function, as well Parkin Pink1, mitochondria quality control, DJ-1, response kinase LRRK2 [4]. onset families these 20 50, considerably earlier than years age, typical sporadic Additionally, involves massive changes metabolism (La Cognata 2015), both (Liu 2017) patients' leukocytes (Soreq 2008, 2012, 2014; 2020), contributions circular risks so far remained unexplored. rediscovered type co-transcriptional circularization exons spliceosome named back-splicing (Memczak 2013; Ashwal-Fluss Jeck Sharpless, Li 2018; Kristensen 2019). They flies, nematodes, mice (Westholm Gruner 2016; Cortes-Lopez 2018), some them enriched synapses dendrites (Rybak-Wolf 2015; Veno You 2015). Most known derived RNA-polymerase II transcription coding genes, structure makes resistant exonucleases hence exceptionally stable molecules compared canonical mRNA (Jeck 2013). Hence, can potentially become biomarkers follow-up treatment efficacy or new therapeutics (Zhang 2018). While thousands described, only few has elucidated. These circCDR1as, abundant mammalian circRNA. CircCDR1as antisense strand cerebellar degeneration-related 1 (CDR1) gene highly (Hansen It binds miR Argonaute2 (Ago2) harbors 73 miR-7 Memczak Initially, it was though CDR1as degrades miR-7. However, knockout results lower, higher miRNA, stability way (Piwecka 2017). This likely non-coding Cyrano (Guo Kleaveland shown functional vivo flies (Holdt Chen 2017; 2017a,2017b; Pamudurti proposed variety functions RBP transport (Ashwal-Fluss 2014), rRNA maturation, miRNA stabilization 2016). Moreover, subset translated no products (Legnini Yang Liang Interestingly, reports suggested disorders Alzheimer's amyotrophic lateral sclerosis (Lukiw, Errichelli Shi Dube Supporting notion, many features, suggest potential demise. called establishing role intriguing transcripts could addressed. production regulated hyper-editing events—higher beyond transcriptome alignment (Porath Ivanov Rybak-Wolf As 99% A-to-I humans occurs elements, those elements may serve measure global (Levanon 2004). transposable genome (over million copies), originated inserted opposite orientations form dsRNA structures, providing substrate adenosine deaminases (ADAR proteins). flanked introns contain repeats postulated mediate generation (Ivanov Multiple pairing events competition formation alternative same locus 2014a,2014b). ADAR negatively correlates neural tissue cell lines regulation complex. On hand, relative location (or repeats) key determining how modulates biogenesis DHX9, helicase inverted-repeat unwinds secondary represses abundance (Aktas whether such relate yet investigated. address determine biomark disease, comprehensively profiled individuals: much PD-related demise takes place, medial temporalis (MTG), (AMG), controls acute accompany Comparing patients matched apparently aged elements. Having significantly upregulated selected in-depth example relates PD-inducing stress. sum, provides important studying demonstrates miss-regulated genomic profiles particular changed PD, sequenced rRNA-depleted RNA-seq libraries AMG, MTG (Fig EV1A–D; see Dataset EV1 clinical data donors). analyzed included 27 42 samples (libraries prepared RIN > 6.5, excluded low circRNAs; Appendix Fig S1E–H). relatively set assisted dealing individual heterogeneity characteristic (Barbash level (50 M reads per sample average; EV1I, EV2), allowing reliable simultaneous detection quantification mRNAs, long (lncRNAs) circRNAs. bioinformatics pipeline identify annotate mRNAs Click here expand figure. Figure EV1. Tissues retrieved experimental in-house methodology A. origin NBB detailing each area. B. Average plot frozen tissues. C. Library preparation steps (see details Materials Methods). D. TapeStation run. E–G. Number detected all 3 regions. Samples < 5,000 removed analysis. H. I. tissue. Download figure PowerPoint An initial analysis non-supervised hierarchical clustering indicated substantial AMG failed distinguish (Figs 11A B, EV2A). reflected individuals; pronounced specificity dominate gender, Braak stage differences, severity, possibly impact diverse medications relevant (Braak 2003). Unlike samples, enabled better separation 11C EV2B–D). might reflect bigger differences due SN. tyrosine hydroxylase (TH) (t-test P = 0.025; 11D), compatible decrease upon 1. indicate multicellular tissues: (blue), (green), (red). Non-supervised heatmap indicates controls. red. PCA (green) (blue). qPCR validation TH controls, normalized beta-actin mRNA. t-test *P 0.025. Data presented mean ± SD. n 18 CT 24 E. Top GO DE vs corresponding logP values, Wald test (DEseq2 analysis). F, G. Venn diagrams demonstrating type-specific tissues, up/down arrows groups regulated. Module–trait relationship WGCNA showing corrected values (in brackets) module (indicated colors) related external traits (disease condition, region, sex). Correlation p value calculated package. Module membership vs. significance modules reflecting traits: condition (reflected brown red modules), (the blue module), sex cyan regression-based 8 15 13 10 J. Significant terms emerged blue, red, log Fisher's exact value. EV2. QC, Substantia heatmap, represented colors, marked color key: Reduction light green elevation blue. C, MTG. Sample dendrogram classification sample. F. Cluster genes. G, log2 fold change −log splicing SD, Walt Global following correction composition (for microglia, astrocytes, neurons, Methods) (e.g., SNCA, TH, DNAJC6, SYNJ1, GBA, SLC6A3) (corrected 0.00048), synapse 2.06E-05) neurodegeneration 0.0017; Miller 2004; Zhang 2005; Moran Simunovic 2009; Lewis Cookson, 2012). Gene Ontology (GO) enrichment differentially (DE) junctions, vesicle 8.52E-04), ion 1.37E-04), biosynthetic 0.0198), 11E, EV3 FDR 0.01 term analysis, EV4 shows detailed terms). next utilized single-cell types expressing (McKenzie 11F G) types, endothelial cells, oligodendrocytes, astrocytes proportion microglia. neuron-specific predictably showed decreases (63 14 chi-square test, 3.5E-12), whereas oligodendrocytes microglia-expressed tendency (24 12 2 brains), fractions elevated inflammation. putative co-regulation performed weighted network (WGCNA; Langfelder Horvath, 2008). closely altered patterns, creating intra-related variability scores EV2E F EV5). Genes clustered into colors 11H, left scale), assessed relationships calculating trait 11H). measured correlations memberships closeness gene's modules. certain module–trait relationships, (PD control), classification,

Язык: Английский

---

The Evolving Understanding of Dopamine Neurons in the Substantia Nigra and Ventral Tegmental Area

Annual Review of Physiology, Год журнала: 2017, Номер 80(1), С. 219 - 241

Опубликована: Сен. 22, 2017

In recent years, the population of neurons in ventral tegmental area (VTA) and substantia nigra (SN) has been examined at multiple levels. The results indicate that projections, neurochemistry, receptor ion channel expression this cell vary widely. This review centers on intrinsic properties synaptic regulation control activity dopamine neurons. Although all fire action potentials a pacemaker pattern absence input, underlie differ considerably. Likewise, transition into burst/pause from combinations conductances, inhibitory excitatory inputs among population. Finally, plasticity is key regulator rate different groups Through these fundamental properties, regulated underlies wide-ranging functions have attributed to dopamine.

Язык: Английский

---

The Potential of L-Type Calcium Channels as a Drug Target for Neuroprotective Therapy in Parkinson's Disease

The Annual Review of Pharmacology and Toxicology, Год журнала: 2019, Номер 59(1), С. 263 - 289

Опубликована: Янв. 6, 2019

The motor symptoms of Parkinson's disease (PD) mainly arise from degeneration dopamine neurons within the substantia nigra. As no disease-modifying PD therapies are available, and side effects limit long-term benefits current symptomatic therapies, novel treatment approaches needed. ongoing phase III clinical study STEADY-PD is investigating potential dihydropyridine isradipine, an L-type Ca2+ channel (LTCC) blocker, for neuroprotective therapy. Here we review preclinical rationale this trial discuss reasons ambiguous outcomes in vivo animal model studies that address PD-protective effects. We summarize views about roles Cav1.2 Cav1.3 LTCC isoforms nigra neuron function, their high vulnerability to degenerative stressors, pathophysiology. different sensitivities view as drug targets neuroprotection, conclude by considering how these aspects could guide further development.

Язык: Английский

---

Cav2.3 channels contribute to dopaminergic neuron loss in a model of Parkinson’s disease

Nature Communications, Год журнала: 2019, Номер 10(1)

Опубликована: Ноя. 8, 2019

Degeneration of dopaminergic neurons in the substantia nigra causes motor symptoms Parkinson's disease. The mechanisms underlying this age-dependent and region-selective neurodegeneration remain unclear. Here we identify Cav2.3 channels as regulators nigral neuronal viability. transcripts were more abundant than other voltage-gated Ca2+ mouse upregulated during aging. Plasmalemmal protein was higher ventral tegmental area, which do not degenerate knockout reduced activity-associated somatic signals Ca2+-dependent after-hyperpolarizations, afforded full protection from degeneration vivo a neurotoxin model. deficiency for NCS-1, Ca2+-binding implicated neuroprotection. Conversely, NCS-1 exacerbated downregulated Cav2.3. Moreover, levels human iPSC-model familial Parkinson's. Thus, may constitute potential therapeutic targets combatting

Язык: Английский

---