DOCSLIB.ORG

A Novel Structure Associated with Aging Is Augmented in the DPP6‑KO Mouse Brain Lin Lin1†, Ronald S

Total Page：16

File Type：pdf, Size：1020Kb

Download full-text PDF Read full-text
A Novel Structure Associated with Aging Is Augmented in the DPP6‑KO Mouse Brain Lin Lin1†, Ronald S Lin et al. acta neuropathol commun (2020) 8:197 https://doi.org/10.1186/s40478-020-01065-7 RESEARCH Open Access A novel structure associated with aging is augmented in the DPP6-KO mouse brain Lin Lin1†, Ronald S. Petralia2†, Ross Lake3, Ya‑Xian Wang2 and Dax A. Hofman1* Abstract In addition to its role as an auxiliary subunit of A‑type voltage‑gated K+ channels, we have previously reported that the sin‑ gle transmembrane protein Dipeptidyl Peptidase Like 6 (DPP6) impacts neuronal and synaptic development. DPP6‑KO mice are impaired in hippocampal‑dependent learning and memory and exhibit smaller brain size. Using immunofuorescence and electron microscopy, we report here a novel structure in hippocampal area CA1 that was signifcantly more prevalent in aging DPP6‑KO mice compared to WT mice of the same age and that these structures were observed earlier in develop‑ ment in DPP6‑KO mice. These novel structures appeared as clusters of large puncta that colocalized NeuN, synaptophysin, and chromogranin A. They also partially labeled for MAP2, and with synapsin‑1 and VGluT1 labeling on their periphery. Elec‑ tron microscopy revealed that these structures are abnormal, enlarged presynaptic swellings flled with mainly fbrous mate‑ rial with occasional peripheral, presynaptic active zones forming synapses. Immunofuorescence imaging then showed that a number of markers for aging and especially Alzheimer’s disease were found as higher levels in these novel structures in aging DPP6‑KO mice compared to WT. Together these results indicate that aging DPP6‑KO mice have increased numbers of novel, abnormal presynaptic structures associated with several markers of Alzheimer’s disease. Keywords: DPP6, Alzheimer’s disease, Aging dementia, Presynaptic terminals Introduction DPP6 to be a novel gene in dementia, fnding enhanced DPP6 is a type II single pass transmembrane protein rare variants and nonsense, frameshift and missense muta- expressed in brain [35, 64], and well known as an auxiliary tions in early Alzheimer’s disease (AD) and frontotemporal subunit of the Kv4 family of voltage-gated K + channels dementia patient cohorts [9]. Another fnding by Zelaya [45], which play a crucial role in neuronal excitability and et al. [77] demonstrated an olfactory progressive proteome plasticity [23, 65]. We previously reported a surprising role modulation in AD, which shows olfactory dysfunction in for DPP6 in hippocampal synaptic development and func- up to 90% of patients. Tey report a specifc late reduction tion that is apparently independent of Kv4.2 [36, 37]. Clini- of DPP6 in the olfactory bulb of patients with AD. Overall, cally, the DPP6 gene has been associated with numerous these fndings provided basic information for understand- intellectual and neurodevelopmental disorders [6, 17, 33, ing possible roles of DPP6 in aging and the pathophysiol- 41, 43, 47, 53, 55, 56]. An important recent study showed ogy of diseases such as AD/dementia. AD is the most common form of major neurocogni- tive disorder (dementia). It is a progressive neurodegen- *Correspondence: [email protected] erative disease associated with memory impairment and † Lin Lin and Ronald S. Petralia contributed equally to this work. cognitive decline. Currently, defnitive diagnoses of AD 1 Molecular Neurophysiology and Biophysics Section, Program in Developmental Neuroscience, Eunice Kennedy Shriver National require post-mortem analysis and there are no curative Institute of Child Health and Human Development, 35 Lincoln Drive, MSC therapies for AD [7, 10, 57]. Diagnostic hallmarks include 3715, Building 35, Room 3C‑905, Bethesda, MD 20892‑3715, USA the abnormal accumulation of extracellular amyloid-β Full list of author information is available at the end of the article © The Author(s) 2020. Open Access This article is licensed under a Creative Commons Attribution 4.0 International License, which permits use, sharing, adaptation, distribution and reproduction in any medium or format, as long as you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons licence, and indicate if changes were made. The images or other third party material in this article are included in the article’s Creative Commons licence, unless indicated otherwise in a credit line to the material. If material is not included in the article’s Creative Commons licence and your intended use is not permitted by statutory regulation or exceeds the permitted use, you will need to obtain permission directly from the copyright holder. To view a copy of this licence, visit http://creat iveco mmons .org/licen ses/by/4.0/. The Creative Commons Public Domain Dedication waiver (http://creat iveco mmons .org/publi cdoma in/zero/1.0/) applies to the data made available in this article, unless otherwise stated in a credit line to the data. Lin et al. acta neuropathol commun (2020) 8:197 Page 2 of 18 peptide (Aβ, amyloid plaques), intracellular neurofbril- structures associated with physical and biochemical mark- lary tangles composed of phosphorylated tau (pTau), and ers for dementia. neuronal loss. Tese abnormalities that characterize AD are particularly prevalent in the hippocampus such that Materials and methods “hippocampal atrophy is one of the earliest detectable Animals symptoms of ongoing neurodegeneration” [42]. Aβ and DPP6-KO and WT mice were weaned at 3 weeks of age, pTau pathologies are associated with neuroinfammation genotyped via PCR, and housed 3–4 mice per cage. Mice characterized by activation of microglia and astrocytes were housed under a 12-h light/dark cycle with the lights of and elevated levels of proinfammatory cytokines [50, 60]. at 18:00. We only used male mice in all experiments. DPP6- In both human patients with early AD and in mouse KO mice were originally from Dr. B. Rudy at NYU School of models of AD, Aβ accumulation precedes and promotes Medicine, New York, and WT C57BL/6 were originally from tau pathology. In human brains with early AD, intraneu- Jackson Laboratory. All animal procedures were performed in ronal Aβ42 accumulation in hippocampal cell bodies accordance with guidelines approved by the National Institute precedes hyperphosphorylation of tau [20, 21], and in a of Child Health and Human Development Animal Care and common mouse model of AD (3xTg-AD mouse), intra- Use Committee and in accordance with NIH guidelines. neuronal Aβ accumulation in cell bodies also precedes tau hyperphosphorylation [48, 49]. Microglia activation Electron microscopy and proliferation around amyloid plaques is also a key Hippocampi were prepared for transmission electron feature in AD pathogenesis. microscope (TEM) study as described previously [32]. Tau proteins stabilize microtubules and play a role in Briefy, WT and DPP6-KO, 12-month old mice were fxed axonal transport and neurite outgrowth [4, 5, 11, 63, 66]. in 4% paraformaldehyde plus 2% glutaraldehyde (Electron Tese functions of tau can be modulated by phosphoryla- Microscopy Sciences (Hatfeld, PA; EMS) in phosphate tion that can be both physiological and pathological to bufer (PB), then washed in PB and vibratomed at 150 µm. the cell. Tere is signifcant evidence that a disruption of Slices were washed in cacodylate bufer and placed in 1% normal phosphorylation events results in tau dysfunction osmium tetroxide in cacodylate bufer, washed again in in neurodegenerative diseases such as AD, and is a con- cacodylate bufer, and dehydrated in an ethanol series with tributing factor to the pathogenic processes [3, 25]. Te 1% uranyl acetate added to the 50% ethanol. Tissue was resulting abnormal tau accumulation in AD/dementia placed in propylene oxide (PO), and then in an epon/PO may lead, for example, to various axonopathies such as mix and fnally in pure epon; then samples were embedded axonal swellings [38, 70]. and hardened in an oven at 64 °C. Tin sections (60 nm) In this study, we examined the cell architecture and were placed on single slot, formvar/carbon coated nickel proteins associated with aging in the hippocampus of grids (EMS), stained with uranyl acetate and lead citrate, DPP6-KO mice, and discovered unique clusters of large and examined in a JEOL JEM2100 TEM (Peabody, MA). NeuN-labelled puncta concentrated throughout the hip- Images were taken from 2 WT and 2 KO mice, in all areas pocampal CA1 region that were larger and more abundant of the CA1, as well as in the molecular layer of the dentate and expressed at earlier ages in DPP6-KO mice compared gyrus. to WT. Tese structures partly colocalized with a num- Mouse hippocampi used for postembedding immuno- ber of proteins associated with AD, including Aβ, pTau, gold localization were prepared as described previously α-synuclein and chromogranin A. Labeling for a number [22, 36, 52, 65]. Briefy, WT and DPP6-KO, 12-month old of markers of AD was higher in the puncta of the DPP6- mice were perfused with phosphate bufer, followed by KO compared to WT, including Aβ, pTau, α-synuclein, perfusion with 4% paraformaldehyde + 0.5% glutaralde- and APP. Immunocytochemical and ultrastructural meth- hyde in phosphate bufer. Fixed brains were vibratomed ods showed that these structures are derived from abnor- at 350 μm, then cryoprotected in glycerol overnight, fro- mal swollen presynaptic terminals and are associated with zen in a Leica EM CPC (Vienna, Austria), and processed postsynaptic dendrites and synapses. We also found immu- and embedded in Lowicryl HM-20 resin in a Leica AFS nocytochemical and biochemical evidence for substantial freeze-substitution instrument. Tin sections were incu- gliosis. Our fndings demonstrate that DPP6, in addition bated in 0.1% sodium borohydride + 50 mM glycine in to its efects on early synapse development appears to be Tris-bufered saline plus 0.1% Triton X-100 (TBST). important for the maintenance of synaptic function during Sections were immersed in 10% normal goat serum aging as its loss leads to an increase in abnormal synaptic (NGS) in TBST, and primary antibody in 1% NGS/TBST Lin et al.
Load more

Recommended publications
  • 1 BETA- and GAMMA-SYNUCLEINS MODULATE SYNAPTIC VESICLE-BINDING of ALPHA-SYNUCLEIN Kathryn E. Carnazza1#, Lauren Komer1#, André
    bioRxiv preprint doi: https://doi.org/10.1101/2020.11.19.390419; this version posted November 20, 2020. The copyright holder for this preprint (which was not certified by peer review) is the author/funder. All rights reserved. No reuse allowed without permission. BETA- AND GAMMA-SYNUCLEINS MODULATE SYNAPTIC VESICLE-BINDING OF ALPHA-SYNUCLEIN Kathryn E. Carnazza1#, Lauren Komer1#, André Pineda1, Yoonmi Na1, Trudy Ramlall2, Vladimir L. Buchman3, David Eliezer2, Manu Sharma1, Jacqueline Burré1,* 1Helen and Robert Appel Alzheimer’s Disease Research Institute, Brain and Mind Research Institute, Weill Cornell Medicine, New York, New York 10021, USA. 2Department of Biochemistry, Weill Cornell Medicine, New York, New York 10021, USA. 3School of Biosciences, Cardiff University, Cardiff CF103AX, UK & Institute of Physiologically Active Compounds Russian Academy of Sciences (IPAC RAS), Chernogolovka 142432, Moscow Region, Russian Federation. #These authors contributed equally to this work. *Correspondence: [email protected] 1 bioRxiv preprint doi: https://doi.org/10.1101/2020.11.19.390419; this version posted November 20, 2020. The copyright holder for this preprint (which was not certified by peer review) is the author/funder. All rights reserved. No reuse allowed without permission. SUMMARY α-Synuclein (αSyn), β-synuclein (βSyn), and γ-synuclein (γSyn) are abundantly expressed in the vertebrate nervous system. αSyn functions in neurotransmitter release via binding to and clustering synaptic vesicles and chaperoning of SNARE-complex assembly. The functions of βSyn and γSyn are unknown. Functional redundancy of the three synucleins and mutual compensation when one synuclein is deleted have been proposed, but with conflicting evidence. Here, we demonstrate that βSyn and γSyn have a reduced affinity towards membranes compared to αSyn, and that direct interaction of βSyn or γSyn with αSyn results in reduced membrane binding of αSyn.
    [Show full text]
  • Analysis of Proteins That Rapidly Change Upon Mechanistic
    crossmark Research © 2016 by The American Society for Biochemistry and Molecular Biology, Inc. This paper is available on line at http://www.mcponline.org Analysis of Proteins That Rapidly Change Upon Mechanistic/Mammalian Target of Rapamycin Complex 1 (mTORC1) Repression Identifies Parkinson Protein 7 (PARK7) as a Novel Protein Aberrantly Expressed in Tuberous Sclerosis Complex (TSC)*□S Farr Niere‡§¶ʈ§§, Sanjeev Namjoshi‡§ §§, Ehwang Song**, Geoffrey A. Dilly‡§¶, Grant Schoenhard‡‡, Boris V. Zemelman‡§¶, Yehia Mechref**, and Kimberly F. Raab-Graham‡§¶ʈ‡‡¶¶ Many biological processes involve the mechanistic/mam- ally alters the expression of proteins associated with malian target of rapamycin complex 1 (mTORC1). Thus, epilepsy, Alzheimer’s disease, and autism spectrum the challenge of deciphering mTORC1-mediated func- disorder—neurological disorders that exhibit elevated tions during normal and pathological states in the central mTORC1 activity. Through a protein–protein interaction nervous system is challenging. Because mTORC1 is at the network analysis, we have identified common proteins core of translation, we have investigated mTORC1 func- shared among these mTORC1-related diseases. One such tion in global and regional protein expression. Activation protein is Parkinson protein 7, which has been implicated of mTORC1 has been generally regarded to promote in Parkinson’s disease, yet not associated with epilepsy, translation. Few but recent works have shown that sup- Alzheimers disease, or autism spectrum disorder. To ver- pression of mTORC1 can also promote local protein syn- ify our finding, we provide evidence that the protein ex- thesis. Moreover, excessive mTORC1 activation during pression of Parkinson protein 7, including new protein diseased states represses basal and activity-induced pro- synthesis, is sensitive to mTORC1 inhibition.
    [Show full text]
  • Reducing Endogenous Α-Synuclein Mitigates the Degeneration of Selective Neuronal Populations in an Alzheimer's Disease Tran
    The Journal of Neuroscience, July 27, 2016 • 36(30):7971–7984 • 7971 Neurobiology of Disease Reducing Endogenous ␣-Synuclein Mitigates the Degeneration of Selective Neuronal Populations in an Alzheimer’s Disease Transgenic Mouse Model X Brian Spencer,1 Paula A. Desplats,1,2 Cassia R. Overk,1 Elvira Valera-Martin,1 Robert A. Rissman,1 Chengbiao Wu,1 Michael Mante,1 Anthony Adame,1 Jazmin Florio,1 Edward Rockenstein,1 and Eliezer Masliah1,2 1Department of Neurosciences and 2Department of Pathology, University of California–San Diego, La Jolla, California 92093 Alzheimer’s disease (AD) is characterized by the progressive accumulation of amyloid ␤ (A␤) and microtubule associate protein tau, leading to the selective degeneration of neurons in the neocortex, limbic system, and nucleus basalis, among others. Recent studies have shown that ␣-synuclein (␣-syn) also accumulates in the brains of patients with AD and interacts with A␤ and tau, forming toxic hetero-oligomers. Although the involvement of ␣-syn has been investigated extensively in Lewy body disease, less is known about the role of this synaptic protein in AD. Here, we found that reducing endogenous ␣-syn in an APP transgenic mouse model of AD prevented the degeneration of cholinergic neurons, ameliorated corresponding deficits, and recovered the levels of Rab3a and Rab5 proteins involved in intracellular transport and sorting of nerve growth factor and brain-derived neurotrophic factor. Together, these results suggest that ␣-syn might participate in mechanisms of vulnerability of selected neuronal populations in AD and that reducing ␣-syn might be a potential approach to protecting these populations from the toxic effects of A␤.
    [Show full text]
  • Fluid Biomarkers for Synaptic Dysfunction and Loss
    BMI0010.1177/1177271920950319Biomarker InsightsCamporesi et al 950319review-article2020 Biomarker Insights Fluid Biomarkers for Synaptic Dysfunction and Loss Volume 15: 1–17 © The Author(s) 2020 Elena Camporesi1 , Johanna Nilsson1, Ann Brinkmalm1, Article reuse guidelines: sagepub.com/journals-permissions 1,2 1,3,4,5 1,2 Bruno Becker , Nicholas J Ashton , Kaj Blennow DOI:https://doi.org/10.1177/1177271920950319 10.1177/1177271920950319 and Henrik Zetterberg1,2,6,7 1Department of Psychiatry and Neurochemistry, Institute of Neuroscience and Physiology, Sahlgrenska Academy, University of Gothenburg, Gothenburg, Sweden. 2Clinical Neurochemistry Laboratory, Sahlgrenska University Hospital, Mölndal, Sweden. 3King’s College London, Institute of Psychiatry, Psychology & Neuroscience, The Maurice Wohl Clinical Neuroscience Institute, London, UK. 4NIHR Biomedical Research Centre for Mental Health & Biomedical Research Unit for Dementia at South London & Maudsley NHS Foundation, London, UK. 5Wallenberg Centre for Molecular and Translational Medicine, Department of Psychiatry and Neurochemistry, Institute of Neuroscience and Physiology, Sahlgrenska Academy, University of Gothenburg, Gothenburg, Sweden. 6Department of Neurodegenerative Disease, UCL Institute of Neurology, London, UK. 7UK Dementia Research Institute at UCL, London, UK. ABSTRACT: Synapses are the site for brain communication where information is transmitted between neurons and stored for memory forma- tion. Synaptic degeneration is a global and early pathogenic event in neurodegenerative
    [Show full text]
  • In Vitro Aggregation Assays for the Characterization of Α-Synuclein Prion-Like Properties
    View metadata, citation and similar papers at core.ac.uk brought to you by CORE provided by SISSA Digital Library REVIEW REVIEW Prion 8:1, 19–32; January/February 2014; © 2014 Landes Bioscience In vitro aggregation assays for the characterization of α-synuclein prion-like properties Joanna Narkiewicz1, Gabriele Giachin1, and Giuseppe Legname1,2,* 1Prion Biology Laboratory; Department of Neuroscience; Scuola Internazionale Superiore di Studi Avanzati (SISSA); Trieste, Italy; 2ELETTRA Laboratory; Sincrotrone Trieste S.C.p.A., Trieste, Italy; Keywords: alpha-synuclein, aggregation, Parkinson disease, prion-like features 14 Aggregation of α-synuclein plays a crucial role in for the protein in protecting neuronal cells against damage. In the pathogenesis of synucleinopathies, a group of particular, α-synuclein may cooperate with the cysteine-string neurodegenerative diseases including Parkinson disease protein-α (CSPα)—a synaptic vesicle protein with co-chaperone (PD), dementia with Lewy bodies (DLB), diffuse Lewy body activity—in preventing neurodegeneration.15 disease (DLBD) and multiple system atrophy (MSA). The Structurally, α-synuclein features an N-terminal domain common feature of these diseases is a pathological deposition (residues 1–60), a central hydrophobic portion denoted as non-Aβ of protein aggregates, known as Lewy bodies (LBs) in the component of Alzheimer diseases amyloid (NAC, residues 61–95) central nervous system. The major component of these and a C-terminal negatively charged region (residues 96–140). aggregates is α-synuclein, a natively unfolded protein, which Both the N-terminal and NAC domains contain six highly may undergo dramatic structural changes resulting in the conserved hexameric (KTKEGV) motifs (Fig. 1A and B).16 In its formation of β-sheet rich assemblies.
    [Show full text]
  • Targeted De-Repression of Neuronal Nrf2 Inhibits Α-Synuclein Accumulation Paul S
    Baxter et al. Cell Death and Disease (2021) 12:218 https://doi.org/10.1038/s41419-021-03507-z Cell Death & Disease ARTICLE Open Access Targeted de-repression of neuronal Nrf2 inhibits α-synuclein accumulation Paul S. Baxter1,2,NóraM.Márkus1,2,OwenDando1,2,3,XinHe1,2,BashayerR.Al-Mubarak1,2, Jing Qiu1,2 and Giles E. Hardingham 1,2 Abstract Many neurodegenerative diseases are associated with neuronal misfolded protein accumulation, indicating a need for proteostasis-promoting strategies. Here we show that de-repressing the transcription factor Nrf2, epigenetically shut- off in early neuronal development, can prevent protein aggregate accumulation. Using a paradigm of α-synuclein accumulation and clearance, we find that the classical electrophilic Nrf2 activator tBHQ promotes endogenous Nrf2- dependent α-synuclein clearance in astrocytes, but not cortical neurons, which mount no Nrf2-dependent transcriptional response. Moreover, due to neuronal Nrf2 shut-off and consequent weak antioxidant defences, electrophilic tBHQ actually induces oxidative neurotoxicity, via Nrf2-independent Jun induction. However, we find that epigenetic de-repression of neuronal Nrf2 enables them to respond to Nrf2 activators to drive α-synuclein clearance. Moreover, activation of neuronal Nrf2 expression using gRNA-targeted dCas9-based transcriptional activation complexes is sufficient to trigger Nrf2-dependent α-synuclein clearance. Thus, targeting reversal of the developmental shut-off of Nrf2 in forebrain neurons may alter neurodegenerative disease trajectory by boosting proteostasis. 1234567890():,; 1234567890():,; 1234567890():,; 1234567890():,; Introduction Importantly, Nrf2 has also recently been found to be The transcription factor Nrf2 is a widely expressed capable of regulating proteostasis, both directly and indir- stress-responsive regulator of several aspects of homo- ectly, through a number of gain- and loss-of-function stu- eostatic physiology.
    [Show full text]
  • Salivary Biomarkers: Future Approaches for Early Diagnosis of Neurodegenerative Diseases
    brain sciences Review Salivary Biomarkers: Future Approaches for Early Diagnosis of Neurodegenerative Diseases Giovanni Schepici 1, Serena Silvestro 1, Oriana Trubiani 2 , Placido Bramanti 1 and Emanuela Mazzon 1,* 1 IRCCS Centro Neurolesi “Bonino-Pulejo”, Via Provinciale Palermo, Contrada Casazza, 98124 Messina, Italy; [email protected] (G.S.); [email protected] (S.S.); [email protected] (P.B.) 2 Department of Medical, Oral and Biotechnological Sciences, University “G. d’Annunzio” Chieti-Pescara, 66100 Chieti, Italy; [email protected] * Correspondence: [email protected]; Tel.: +39-090-6012-8172 Received: 24 March 2020; Accepted: 19 April 2020; Published: 21 April 2020 Abstract: Many neurological diseases are characterized by progressive neuronal degeneration. Early diagnosis and new markers are necessary for prompt therapeutic intervention. Several studies have aimed to identify biomarkers in different biological liquids. Furthermore, it is being considered whether saliva could be a potential biological sample for the investigation of neurodegenerative diseases. This work aims to provide an overview of the literature concerning biomarkers identified in saliva for the diagnosis of neurodegenerative diseases such as Alzheimer’s disease (AD), Parkinson’s disease (PD), amyotrophic lateral sclerosis (ALS), and multiple sclerosis (MS). Specifically, the studies have revealed that is possible to quantify beta-amyloid1–42 and TAU protein from the saliva of AD patients. Instead, alpha-synuclein and protein deglycase (DJ-1) have been identified as new potential salivary biomarkers for the diagnosis of PD. Nevertheless, future studies will be needed to validate these salivary biomarkers in the diagnosis of neurological diseases. Keywords: salivary biomarkers; Alzheimer’s disease; Parkinson’s disease; amyotrophic lateral sclerosis; multiple sclerosis 1.
    [Show full text]
  • The Neural Chaperone Prosaas Blocks Α-Synuclein Fibrillation and Neurotoxicity
    The neural chaperone proSAAS blocks α-synuclein fibrillation and neurotoxicity Timothy S. Jarvelaa, Hoa A. Lamb, Michael Helwiga,1, Nikolai Lorenzenc,2, Daniel E. Otzenc, Pamela J. McLeand, Nigel T. Maidmentb, and Iris Lindberga,3 aSchool of Medicine, University of Maryland, Baltimore, MD 21201; bDepartment of Psychiatry and Biobehavioral Sciences, Semel Institute for Neuroscience and Human Behavior, University of California, Los Angeles, CA 90024; cInterdisciplinary Nanoscience Centre (iNANO), Department of Molecular Biology and Genetics, Aarhus University, DK-8000 Aarhus C, Denmark; and dDepartment of Neuroscience, Mayo Clinic, Jacksonville, FL 32224 Edited by Solomon H. Snyder, The Johns Hopkins University School of Medicine, Baltimore, MD, and approved June 14, 2016 (received for review January 20, 2016) Emerging evidence strongly suggests that chaperone proteins are the proprotein convertase PC1/3 (23, 24), proSAAS distribution cytoprotective in neurodegenerative proteinopathies involving pro- within the brain is far wider than that of PC1/3 (20, 21). ProSAAS tein aggregation; for example, in the accumulation of aggregated and PC1/3 expression are also not coregulated (25, 26), supporting a α-synuclein into the Lewy bodies present in Parkinson’sdisease.Of broader array of neuronal functions for proSAAS beyond its in- the various chaperones known to be associated with neurodegener- teractionwithPC1/3. ative disease, the small secretory chaperone known as proSAAS Interestingly, the proSAAS protein has been increasingly asso- (named after four residues in the amino terminal region) has many ciated with the presence of neurodegenerative disease. Immuno- attractive properties. We show here that proSAAS, widely expressed reactive proSAAS has been identified in neurofibrillary tangles in neurons throughout the brain, is associated with aggregated syn- and plaques in brain tissue from patients with Alzheimer’sdisease, uclein deposits in the substantia nigra of patients with Parkinson’s Pick’s disease, and Parkinsonism–dementia complex (27, 28).
    [Show full text]
  • Neural Activity Controls the Synaptic Accumulation Ofα-Synuclein
    The Journal of Neuroscience, November 23, 2005 • 25(47):10913–10921 • 10913 Neurobiology of Disease Neural Activity Controls the Synaptic Accumulation of ␣-Synuclein Doris L. Fortin,1 Venu M. Nemani,1 Susan M. Voglmaier,1 Malcolm D. Anthony,1 Timothy A. Ryan,2 and Robert H. Edwards1 1Departments of Neurology and Physiology, Graduate Programs in Biomedical Sciences, Cell Biology, and Neuroscience, University of California, San Francisco, San Francisco, California 94143-2140, and 2Department of Biochemistry, Weill Medical College of Cornell University, New York, New York 10021 The presynaptic protein ␣-synuclein has a central role in Parkinson’s disease (PD). However, the mechanism by which the protein contributes to neurodegeneration and its normal function remain unknown. ␣-Synuclein localizes to the nerve terminal and interacts with artificial membranes in vitro but binds weakly to native brain membranes. To characterize the membrane association of ␣-synuclein in living neurons, we used fluorescence recovery after photobleaching. Despite its enrichment at the synapse, ␣-synuclein is highly mobile, with rapid exchange between adjacent synapses. In addition, we find that ␣-synuclein disperses from the nerve terminal in response to neural activity. Dispersion depends on exocytosis, but unlike other synaptic vesicle proteins, ␣-synuclein dissociates from the synaptic vesicle membrane after fusion. Furthermore, the dispersion of ␣-synuclein is graded with respect to stimulus intensity. Neural activity thus controls the normal function of ␣-synuclein at the nerve terminal and may influence its role in PD. Key words: ␣-synuclein; membrane association; synaptic vesicle; neural activity; Parkinson’s disease; synapsin Introduction et al., 2000; Chandra et al., 2004) but rather, increases in dopa- Genetic studies have implicated the protein ␣-synuclein in the mine release (Abeliovich et al., 2000; Yavich et al., 2004).
    [Show full text]
  • Synaptic Regulator Α-Synuclein in Dopaminergic Fibers Is Essentially Required for the Maintenance of Subependymal Neural Stem C
    814 • The Journal of Neuroscience, January 24, 2018 • 38(4):814–825 Development/Plasticity/Repair Synaptic Regulator ␣-Synuclein in Dopaminergic Fibers Is Essentially Required for the Maintenance of Subependymal Neural Stem Cells X Ana Perez-Villalba,1,2,3 M. Salome´ Sirerol-Piquer,1,2,3 Germa´n Belenguer,1,2,3 Rau´l Soriano-Canto´n,1,2,3 X Ana Bele´n Mun˜oz-Manchado,1,4,5 XJavier Villadiego,1,4,5 XDiana Alarco´n-Arís,6,7,8 XFederico N. Soria,9,10 X Benjamin Dehay,9,10 XErwan Bezard,9,10 Miquel Vila,1,11,12 XAnalía Bortolozzi,6,7,8 XJuan Jose´ Toledo-Aral,1,4,5 Francisco Pe´rez-Sa´nchez,1,2,3 and XIsabel Farin˜as1,2,3 1Centro de Investigacio´n Biome´dica en Red de Enfermedades Neurodegenerativas, ISCIII, 28029 Madrid, Spain, 2Departamento de Biología Celular, Biología Funcional y Antropología Física and 3Estructura de Recerca Interdisciplinar en Biotecnologia i Biomedicina, Universidad de Valencia, 46100 Burjassot, Spain, 4Departamento de Fisiología Me´dica y Biofísica and 5Instituto de Biomedicina de Sevilla, Hospital Universitario Virgen del Rocío/CSIC/ Universidad de Sevilla, 41013 Sevilla, Spain, 6Department of Neurochemistry and Neuropharmacology, IIBB-CSIC and 7Institut d’Investigacions Biome`diques August Pi i Sunyer, 08036 Barcelona, Spain, 8Centro de Investigacio´n Biome´dica en Red de Salud Mental, ISCIII, 28029 Madrid, Spain, 9Universite´ de Bordeaux, Institut des Maladies Neurode´ge´ne´ratives, Unite´ Mixte de Recherche 5293 and 10Centre National de la Recherche Scientifique, Institut des Maladies Neurode´ge´ne´ratives, Unite´ Mixte de Recherche 5293, 33076 Bordeaux, France, 11Neurodegenerative Diseases Research Group, Vall dЈHebron Research Institute, Autonomous University of Barcelona, 08035, Barcelona, Spain, and 12Catalan Institution for Research and Advanced Studies, 08010 Barcelona, Spain Synaptic protein ␣-synuclein (␣-SYN) modulates neurotransmission in a complex and poorly understood manner and aggregates in the cytoplasm of degenerating neurons in ParkinsonЈs disease.
    [Show full text]
  • Synuclein - a Possible Initiator of Inflammation in Parkinson’S Disease
    REVIEW Institute of Neurosurgery, The PLA Navy General Hospital, Beijing, China Extracellular ␣-synuclein - a possible initiator of inflammation in Parkinson’s disease Wen-Qing Ren, Zeng-Min Tian, Feng Yin, Jun-Zhao Sun, Jian-Ning Zhang Received April 18, 2015, accepted July 17, 2015 Jian-Ning Zhang, Institute of Neurosurgery, General Hospital of Navy, 6 Fucheng Rd., Beijing 100048, China [email protected] Pharmazie 71: 51–55 (2016) doi: 10.1691/ph.2016.5070 Parkinson’s disease (PD) is a progressive neurodegenerative disease involving the loss of dopamine- producing neurons of the substantia nigra and the presence of Lewy bodies which contain high levels of ␣-synuclein. Although the causative factors of PD remain unclear, the progression of PD is accompanied by a highly localized inflammatory response mediated by reactive microglia. Recently, attention has focused on the relationship between ␣-synuclein and microglial activation. This review examines the role of ␣-synuclein on microglia in PD pathogenesis and progression, we also discuss the way of ␣-synuclein induced microglial activation. 1. Introduction 2. Structure and function of ␣-synuclein in PD Parkinson’s disease (PD) is the second most prevalent age- ␣-Synuclein is an abundant and intrinsically disordered pro- related neurodegenerative disease, after Alzheimer’s disease tein that is predominantly localized around synaptic vesicles in (AD). PD affects 3% of people over 60 years (Chauhan and presynatic terminals. ␣-Synuclein is a small protein (140 amino Jeans 2015). The pathological hallmarks of PD are the loss of acid) firstly described in Torpedo californica (Maroteaux et al. dopaminergic neurons in the substantia nigra of the brain and the 1988).
    [Show full text]
  • The Role of Α-Synuclein in the Pathology of Murine
    The role of -synuclein in the pathology of murine Mucopolysaccharidosis type IIIA Kyaw Kyaw Soe (MBBS, MSc) Lysosomal Diseases Research Unit South Australian Health and Medical Research Institute and Department of Paediatrics School of Medicine, Faculty of Health Sciences University of Adelaide Thesis submitted for the degree of Doctor of Philosophy January 2017 TABLE OF CONTENTS List of abbreviations VIII Thesis abstract IX Declaration XI Acknowledgements XII Chapter (1): Introduction and preliminary review 1.1 General introduction 1 1.2 The lysosome and its functions 2 1.3 Biosynthesis of lysosomal enzymes 5 1.4 Functions of mannose-6-phosphate receptors 5 1.5 Lysosomal storage disorders 6 1.6 The mucopolysaccharidoses (MPS) 6 1.7 Sanfilippo syndrome 9 1.8 Sanfilippo syndrome type A (MPS type IIIA) 10 1.9 Clinical presentations of Sanfilippo syndrome 13 1.10 Diagnosis and therapeutic approaches for MPS disorders 15 1.11 MPS IIIA animal models 16 1.12 Primary storage pathology: glycosaminoglycans 18 1.12.1 Structure and functions of glycosaminoglycans 18 1.12.2 Degradation of glycosaminoglycans 19 1.12.3 Heparan sulphate metabolism 19 1.13 Secondary pathology 23 1.13.1 Gangliosides, microglia, neuroinflammation and cell death 23 1.13.2 Secondary proteinaceous accumulation 24 1.13.3 -Synuclein accumulation in lysosomal storage disorders 25 1.14 Cellular protein degradation pathways 26 1.15 The synuclein family 30 1.16 The -synuclein protein 31 II 1.16.1 Structure and location of -synuclein 31 1.16.2 Structural components of -synuclein
    [Show full text]