scholarly journals Haploinsufficiency of Parkinsonism Gene SYNJ1 Contributes to Dopamine neuron Vulnerability in Aged Mice

2017 ◽  
Author(s):  
Ping-Yue Pan ◽  
Patricia Sheehan ◽  
Qian Wang ◽  
Yuanxi Zhang ◽  
Jing Wang ◽  
...  
Keyword(s):  
Neurodegenerative Disorder ◽  
Behavioral Alterations ◽  
Aged Mice ◽  
Vesicle Recycling ◽  
Recessive Mutations ◽  
Risk Variants ◽  
Daergic Neuron ◽  
Age Dependent ◽  
Terminal Degeneration

AbstractParkinson’s disease (PD) is an age-dependent neurodegenerative disorder characterized by the loss of substantia nigra dopaminergic (DAergic) neurons in ventral midbrain (MB). Identification of interactions between aging and the known risk variants is crucial to understanding the etiology of PD. Recessive mutations in SYNJ1 have recently been linked to familial early-onset atypical Parkinsonism. We now show an age-dependent decline of SYNJ1 expression in the striatum as well as in striatal DAergic terminals of aged mice. Heterozygous deletion of SYNJ1 in mice causes selective elevation of PIP2 in the MB, and manipulation of PIP2 levels also impairs synaptic vesicle recycling preferentially in MB neurons. SYNJ1+/− mice display progressive PD-like behavioral alterations and DAergic terminal degeneration. Furthermore, we found down-regulation of human SYNJ1 transcripts in a subset of sporadic PD brains, corroborating the role of an age-dependent decrease in SYNJ1 in predisposing DAergic neuron vulnerability and PD pathogenesis.

scholarly journals Age-dependent emergence of neurophysiological and behavioral abnormalities in progranulin-deficient mice

2019 ◽  
Vol 11 (1) ◽  
Author(s):  
Dávid Nagy ◽  
Lauren Herl Martens ◽  
Liza Leventhal ◽  
Angela Chen ◽  
Craig Kelley ◽  
...  
Keyword(s):  
Frontotemporal Dementia ◽  
Neurodegenerative Disorder ◽  
Neuronal Loss ◽  
Loss Of Function ◽  
Behavioral Alterations ◽  
Response Latencies ◽  
Reward Seeking ◽  
Behavioral Abnormalities ◽  
Age Dependent

Abstract Background Loss-of-function mutations in the progranulin gene cause frontotemporal dementia, a genetic, heterogeneous neurodegenerative disorder. Progranulin deficiency leads to extensive neuronal loss in the frontal and temporal lobes, altered synaptic connectivity, and behavioral alterations. Methods The chronological emergence of neurophysiological and behavioral phenotypes of Grn heterozygous and homozygous mice in the dorsomedial thalamic—medial prefrontal cortical pathway were evaluated by in vivo electrophysiology and reward-seeking/processing behavior, tested between ages 3 and 12.5 months. Results Electrophysiological recordings identified a clear age-dependent deficit in the thalamocortical circuit. Both heterozygous and homozygous mice exhibited impaired input-output relationships and paired-pulse depression, but evoked response latencies were only prolonged in heterozygotes. Furthermore, we demonstrate firstly an abnormal reward-seeking/processing behavior in the homozygous mice which correlates with previously reported neuroinflammation. Conclusion Our findings indicate that murine progranulin deficiency causes age-dependent neurophysiological and behavioral abnormalities thereby indicating their validity in modeling aspects of human frontotemporal dementia.

scholarly journals Synj1 haploinsufficiency causes dopamine neuron vulnerability and alpha-synuclein accumulation in mice

2020 ◽  
Vol 29 (14) ◽  
pp. 2300-2312 ◽  
Author(s):  
Ping-Yue Pan ◽  
Patricia Sheehan ◽  
Qian Wang ◽  
Xinyu Zhu ◽  
Yuanxi Zhang ◽  
...  
Keyword(s):  
Alpha Synuclein ◽  
Midbrain Neurons ◽  
Phosphoinositide Phosphatase ◽  
Phospholipid Signaling ◽  
Age Dependent ◽  
Terminal Degeneration ◽  
Trafficking Defects ◽  
The Brain ◽  
Dopaminergic Terminal

Abstract Synaptojanin1 (synj1) is a phosphoinositide phosphatase with dual SAC1 and 5′-phosphatase enzymatic activities in regulating phospholipid signaling. The brain-enriched isoform has been shown to participate in synaptic vesicle (SV) recycling. More recently, recessive human mutations were identified in the two phosphatase domains of SYNJ1, including R258Q, R459P and R839C, which are linked to rare forms of early-onset Parkinsonism. We now demonstrate that Synj1 heterozygous deletion (Synj1+/−), which is associated with an impaired 5′-phosphatase activity, also leads to Parkinson’s disease (PD)-like pathologies in mice. We report that male Synj1+/− mice display age-dependent motor function abnormalities as well as alpha-synuclein accumulation, impaired autophagy and dopaminergic terminal degeneration. Synj1+/− mice contain elevated 5′-phosphatase substrate, PI(4,5)P2, particularly in the midbrain neurons. Moreover, pharmacological elevation of membrane PI(4,5)P2 in cultured neurons impairs SV endocytosis, specifically in midbrain neurons, and further exacerbates SV trafficking defects in Synj1+/− midbrain neurons. We demonstrate down-regulation of SYNJ1 transcript in a subset of sporadic PD brains, implicating a potential role of Synj1 deficiency in the decline of dopaminergic function during aging.

Peripheral Immunity, Immunoaging and Neuroinflammation in Parkinson’s Disease

2019 ◽  
Vol 26 (20) ◽  
pp. 3719-3753 ◽  
Author(s):  
Natasa Kustrimovic ◽  
Franca Marino ◽  
Marco Cosentino
Keyword(s):  
Parkinson’S Disease ◽  
Parkinson's Disease ◽  
Immune System ◽  
Neurodegenerative Disorder ◽  
Neurodegenerative Process ◽  
Progressive Degeneration ◽  
Cytokine Levels ◽  
Inflammatory Phenotype ◽  
Immune Challenges

:Parkinson’s disease (PD) is the second most common neurodegenerative disorder among elderly population, characterized by the progressive degeneration of dopaminergic neurons in the midbrain. To date, exact cause remains unknown and the mechanism of neurons death uncertain. It is typically considered as a disease of central nervous system (CNS). Nevertheless, numerous evidence has been accumulated in several past years testifying undoubtedly about the principal role of neuroinflammation in progression of PD. Neuroinflammation is mainly associated with presence of activated microglia in brain and elevated levels of cytokine levels in CNS. Nevertheless, active participation of immune system as well has been noted, such as, elevated levels of cytokine levels in blood, the presence of auto antibodies, and the infiltration of T cell in CNS. Moreover, infiltration and reactivation of those T cells could exacerbate neuroinflammation to greater neurotoxic levels. Hence, peripheral inflammation is able to prime microglia into pro-inflammatory phenotype, which can trigger stronger response in CNS further perpetuating the on-going neurodegenerative process.:In the present review, the interplay between neuroinflammation and the peripheral immune response in the pathobiology of PD will be discussed. First of all, an overview of regulation of microglial activation and neuroinflammation is summarized and discussed. Afterwards, we try to collectively analyze changes that occurs in peripheral immune system of PD patients, suggesting that these peripheral immune challenges can exacerbate the process of neuroinflammation and hence the symptoms of the disease. In the end, we summarize some of proposed immunotherapies for treatment of PD.

Microglia in Alzheimer’s Disease

2020 ◽  
Vol 17 (1) ◽  
pp. 29-43 ◽  
Author(s):  
Patrick Süß ◽  
Johannes C.M. Schlachetzki
Keyword(s):  
Alzheimer’S Disease ◽  
Alzheimer's Disease ◽  
Neurodegenerative Disorder ◽  
Current Knowledge ◽  
Imaging Techniques ◽  
Amyloid Β ◽  
Disease Stage ◽  
Disease Modifying Therapy ◽  
Transcriptomic Signature

: Alzheimer’s Disease (AD) is the most frequent neurodegenerative disorder. Although proteinaceous aggregates of extracellular Amyloid-β (Aβ) and intracellular hyperphosphorylated microtubule- associated tau have long been identified as characteristic neuropathological hallmarks of AD, a disease- modifying therapy against these targets has not been successful. An emerging concept is that microglia, the innate immune cells of the brain, are major players in AD pathogenesis. Microglia are longlived tissue-resident professional phagocytes that survey and rapidly respond to changes in their microenvironment. Subpopulations of microglia cluster around Aβ plaques and adopt a transcriptomic signature specifically linked to neurodegeneration. A plethora of molecules and pathways associated with microglia function and dysfunction has been identified as important players in mediating neurodegeneration. However, whether microglia exert either beneficial or detrimental effects in AD pathology may depend on the disease stage. : In this review, we summarize the current knowledge about the stage-dependent role of microglia in AD, including recent insights from genetic and gene expression profiling studies as well as novel imaging techniques focusing on microglia in human AD pathology and AD mouse models.

scholarly journals Chondroitin 6-sulphate is required for neuroplasticity and memory in ageing

2021 ◽  
Author(s):  
Sujeong Yang ◽  
Sylvain Gigout ◽  
Angelo Molinaro ◽  
Yuko Naito-Matsui ◽  
Sam Hilton ◽  
...  
Keyword(s):  
Chondroitin Sulphate ◽  
Memory Loss ◽  
Memory Deficits ◽  
Long Term Potentiation ◽  
Aged Mice ◽  
Age Related ◽  
Term Potentiation ◽  
Early Memory

AbstractPerineuronal nets (PNNs) are chondroitin sulphate proteoglycan-containing structures on the neuronal surface that have been implicated in the control of neuroplasticity and memory. Age-related reduction of chondroitin 6-sulphates (C6S) leads to PNNs becoming more inhibitory. Here, we investigated whether manipulation of the chondroitin sulphate (CS) composition of the PNNs could restore neuroplasticity and alleviate memory deficits in aged mice. We first confirmed that aged mice (20-months) showed memory and plasticity deficits. They were able to retain or regain their cognitive ability when CSs were digested or PNNs were attenuated. We then explored the role of C6S in memory and neuroplasticity. Transgenic deletion of chondroitin 6-sulfotransferase (chst3) led to a reduction of permissive C6S, simulating aged brains. These animals showed very early memory loss at 11 weeks old. Importantly, restoring C6S levels in aged animals rescued the memory deficits and restored cortical long-term potentiation, suggesting a strategy to improve age-related memory impairment.

scholarly journals Chloroplast Hsp70 Isoform Is Required for Age-Dependent Tissue Preference of Bamboo mosaic virus in Mature Nicotiana benthamiana Leaves

2017 ◽  
Vol 30 (8) ◽  
pp. 631-645 ◽  
Author(s):  
Ying Wen Huang ◽  
Chung Chi Hu ◽  
Ching Hsiu Tsai ◽  
Na Sheng Lin ◽  
Yau Heiu Hsu
Keyword(s):  
Mosaic Virus ◽  
Nicotiana Benthamiana ◽  
Transit Peptide ◽  
Plant Viruses ◽  
Age Dependent ◽  
Efficient Replication ◽  
Underlying Mechanisms ◽  
Lines Of Evidence ◽  
Suitable Environment

Plant viruses may exhibit age-dependent tissue preference in their hosts but the underlying mechanisms are not well understood. In this study, we provide several lines of evidence to reveal the determining role of a protein of the Nicotiana benthamiana chloroplast Hsp70 (NbcpHsp70) family, NbcpHsp70-2, involved in the preference of Bamboo mosaic virus (BaMV) to infect older tissues. NbcpHsp70 family proteins were identified in complexes pulled down with BaMV replicase as the bait. Among the isoforms of NbcpHsp70, only the specific silencing of NbcpHsp70-2 resulted in the significant decrease of BaMV RNA in N. benthamiana protopalsts, indicating that NbcpHsp70-2 is involved in the efficient replication of BaMV RNA. We further identified the age-dependent import regulation signal contained in the transit peptide of NbcpHsp70-2. Deletion, overexpression, and substitution experiments revealed that the signal in the transit peptide of NbcpHsp70-2 is crucial for both the import of NbcpHsp70-2 into older chloroplasts and the preference of BaMV for infecting older leaves of N. benthamiana. Together, these data demonstrated that BaMV may exploit a cellular age-dependent transportation mechanism to target a suitable environment for viral replication.

scholarly journals Chimeric elk/mouse prion proteins in transgenic mice

2013 ◽  
Vol 94 (2) ◽  
pp. 443-452 ◽  
Author(s):  
Gültekin Tamgüney ◽  
Kurt Giles ◽  
Abby Oehler ◽  
Natrina L. Johnson ◽  
Stephen J. DeArmond ◽  
...  
Keyword(s):  
Neurodegenerative Disorder ◽  
Prion Proteins ◽  
Second Line ◽  
Mouse Line ◽  
Wasting Disease ◽  
C Terminus ◽  
Incubation Periods ◽  
N Terminus ◽  
Mouse Lines

Chronic wasting disease (CWD) of deer and elk is a highly communicable neurodegenerative disorder caused by prions. Investigations of CWD are hampered by slow bioassays in transgenic (Tg) mice. Towards the development of Tg mice that will be more susceptible to CWD prions, we created a series of chimeric elk/mouse transgenes that encode the N terminus of elk PrP (ElkPrP) up to residue Y168 and the C terminus of mouse PrP (MoPrP) beyond residue 169 (mouse numbering), designated Elk3M(SNIVVK). Between codons 169 and 219, six residues distinguish ElkPrP from MoPrP: N169S, T173N, V183I, I202V, I214V and R219K. Using chimeric elk/mouse PrP constructs, we generated 12 Tg mouse lines and determined incubation times after intracerebral inoculation with the mouse-passaged RML scrapie or Elk1P CWD prions. Unexpectedly, one Tg mouse line expressing Elk3M(SNIVVK) exhibited incubation times of <70 days when inoculated with RML prions; a second line had incubation times of <90 days. In contrast, mice expressing full-length ElkPrP had incubation periods of >250 days for RML prions. Tg(Elk3M,SNIVVK) mice were less susceptible to CWD prions than Tg(ElkPrP) mice. Changing three C-terminal mouse residues (202, 214 and 219) to those of elk doubled the incubation time for mouse RML prions and rendered the mice resistant to Elk1P CWD prions. Mutating an additional two residues from mouse to elk at codons 169 and 173 increased the incubation times for mouse prions to >300 days, but made the mice susceptible to CWD prions. Our findings highlight the role of C-terminal residues in PrP that control the susceptibility and replication of prions.

Abstract 65: Restoration of Growth Differentiation Factor 11 Protects Against Stroke in Mice

Stroke ◽  
2016 ◽  
Vol 47 (suppl_1) ◽  
Author(s):  
Anjali Chauhan ◽  
Jacob Hudobenko ◽  
Anthony Patrizz ◽  
Louise D McCullough
Keyword(s):  
Transforming Growth Factor ◽  
Transforming Growth Factor Β ◽  
The Elderly ◽  
Vehicle Group ◽  
Peripheral Tissues ◽  
Delayed Treatment ◽  
Aged Mice ◽  
Infarct Area ◽  
Age Related

Introduction: GDF 11 is a member of the transforming growth factor β superfamily. Loss of GDF11 occurs with aging and declining levels correlate with several detrimental age-associated phenotypes in both peripheral tissues and brain. Restoration of GDF11 enhances neurogenesis and cognitive function in aged mice. Brain expression of GDF11 has not been investigated after stroke. Stroke differentially affects the elderly. In this work we examined the role of GDF11 in aging, stroke and its potential utility as a neuroprotective agent. Methods: Male C57/BL6NCrl young (2-3 months) and aged (19-21) mice were used. Brain GDF11 expression was evaluated in young and aged mice by western blot. Focal ischemia was induced with a transient middle cerebral artery occlusion (MCAO). Mice were randomly assigned into two groups and were subjected to 90 min MCAO. Group 1 received vehicle (phosphate buffered saline) and group 2 was administered rGDF11 (100 ug/kg., ip) at the onset of ischemia. In additional experiments, the efficacy of delayed treatment (3 h after ischemia) with rGDF11 was tested. These mice were subjected to a 60 min MCAO. Mice were euthanized after 24 hours and 7 days respectively and brains were harvested to estimate infarct area. Results: A significant decrease in brain GDF11 levels was observed in aged mice as compared to young (p<0.05). Additionally, a significant decline in brain GDF11 expression was observed after stroke at 24 hours vs. sham groups (p<0.05). A significant decrease in cortical and hemispheric infarct area was observed in the rGDF11 group (cortical 48.73±1.05; hemisphere 49.68±3.58) as compared to vehicle group (60.54±4.88; 61.35±6.03), when GDF was administered at the time of ischemia. Delayed treatment with rGDF11 also reduced infarct at 7 days. Conclusions: Brain GDF11 levels decline with age and after stroke. Supplementation with rGDF11 ameliorates stroke induced injury in young mice at 24h and 7 days. These finding suggest potential role of GDF11 in age and stroke. Restoration of age-related loss of GDF may be a viable therapy for stroke.

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