Aplp1 and the Aplp1-Lag3 Complex facilitates transmission of pathologic alpha-synuclein

2021 ◽  
Author(s):  
Xiaobo Mao ◽  
Hao Gu ◽  
Donghoon Kim ◽  
Yasuyoshi Kimura ◽  
Ning Wang ◽  
...  
Keyword(s):  
Parkinson Disease ◽  
Molecular Mechanism ◽  
Amyloid Beta ◽  
Dopaminergic Neurons ◽  
Lymphocyte Activation ◽  
Alpha Synuclein ◽  
Therapeutic Strategies ◽  
Behavioral Deficits ◽  
Lymphocyte Activation Gene

Pathologic alpha-synuclein (alpha-syn) spreads from cell-to-cell, in part, through binding to the lymphocyte-activation gene 3 (Lag3). Here we report that amyloid beta precursor-like protein 1 (Aplp1) forms a complex with Lag3 that facilitates the binding, internalization, transmission, and toxicity of pathologic alpha-syn. Deletion of both Aplp1 and Lag3 eliminates the loss of dopaminergic neurons and the accompanying behavioral deficits induced by alpha-syn preformed fibrils (PFF). Anti-Lag3 prevents the internalization of alpha-syn PFF by disrupting the interaction of Aplp1 and Lag3, and blocks the neurodegeneration induced by alpha-syn PFF in vivo. The identification of Aplp1 and the interplay with Lag3 for alpha-syn PFF induced pathology advances our understanding of the molecular mechanism of cell-to-cell transmission of pathologic alpha-syn and provides additional targets for therapeutic strategies aimed at preventing neurodegeneration in Parkinson disease and related alpha-synucleinopathies.

scholarly journals The C-Terminal Domain of LRRK2 with the G2019S Substitution Increases Mutant A53T α-Synuclein Toxicity in Dopaminergic Neurons In Vivo

2021 ◽  
Vol 22 (13) ◽  
pp. 6760
Author(s):  
Noémie Cresto ◽  
Camille Gardier ◽  
Marie-Claude Gaillard ◽  
Francesco Gubinelli ◽  
Pauline Roost ◽  
...  
Keyword(s):  
Dopaminergic Neurons ◽  
Alpha Synuclein ◽  
Post Injection ◽  
Terminal Portion ◽  
Contrast Injection ◽  
Neuron Degeneration ◽  
Terminal Domain ◽  
G2019s Mutation ◽  
A53t Mutation

Alpha-synuclein (α-syn) and leucine-rich repeat kinase 2 (LRRK2) play crucial roles in Parkinson’s disease (PD). They may functionally interact to induce the degeneration of dopaminergic (DA) neurons via mechanisms that are not yet fully understood. We previously showed that the C-terminal portion of LRRK2 (ΔLRRK2) with the G2019S mutation (ΔLRRK2G2019S) was sufficient to induce neurodegeneration of DA neurons in vivo, suggesting that mutated LRRK2 induces neurotoxicity through mechanisms that are (i) independent of the N-terminal domains and (ii) “cell-autonomous”. Here, we explored whether ΔLRRK2G2019S could modify α-syn toxicity through these two mechanisms. We used a co-transduction approach in rats with AAV vectors encoding ΔLRRK2G2019S or its “dead” kinase form, ΔLRRK2DK, and human α-syn with the A53T mutation (AAV-α-synA53T). Behavioral and histological evaluations were performed at 6- and 15-weeks post-injection. Results showed that neither form of ΔLRRK2 alone induced the degeneration of neurons at these post-injection time points. By contrast, injection of AAV-α-synA53T alone resulted in motor signs and degeneration of DA neurons. Co-injection of AAV-α-synA53T with AAV-ΔLRRK2G2019S induced DA neuron degeneration that was significantly higher than that induced by AAV-α-synA53T alone or with AAV-ΔLRRK2DK. Thus, mutated α-syn neurotoxicity can be enhanced by the C-terminal domain of LRRK2G2019 alone, through cell-autonomous mechanisms.

scholarly journals Lymphocyte Activation Gene-3 (CD223) Regulates the Size of the Expanding T Cell Population Following Antigen Activation In Vivo

2004 ◽  
Vol 172 (9) ◽  
pp. 5450-5455 ◽  
Author(s):  
Creg J. Workman ◽  
Linda S. Cauley ◽  
In-Jeong Kim ◽  
Marcia A. Blackman ◽  
David L. Woodland ◽  
...  
Keyword(s):  
T Cell ◽  
Cell Population ◽  
Lymphocyte Activation ◽  
Lymphocyte Activation Gene

Gene of the month: lymphocyte-activation gene 3 (LAG-3)

2021 ◽  
pp. jclinpath-2021-207517
Author(s):  
Mark P Lythgoe ◽  
Daniel Si Kit Liu ◽  
Nicola E Annels ◽  
Jonathan Krell ◽  
Adam Enver Frampton
Keyword(s):  
Mhc Class Ii ◽  
Checkpoint Inhibitors ◽  
Specific Binding ◽  
Cell Signalling ◽  
Lymphocyte Activation ◽  
B Cell Lymphoma ◽  
Activated T Lymphocytes ◽  
T Cell Signalling ◽  
Lymphocyte Activation Gene

Lymphocyte-activation gene 3 (LAG-3) is a coreceptor found on activated T-lymphocytes activated B-lymphocytes and natural killer (NK) cells. It is closely related to CD4 where it shares multiple common and divergent features. It contains specific binding sites with high affinity to major histocompatibility complex (MHC) Class II and functions as an inhibitor of T-cell signalling. Tumour-infiltrating lymphocytes with high LAG-3 expression have been found in many solid tumours including ovarian cancer, melanoma, colorectal cancer and haematological malignancies including Hodgkin and diffuse large B-cell lymphoma. LAG-3 antagonism has been demonstrated to restore the anti-tumourigenic function of T-cells in vivo, however, mechanistic knowledge remains relatively poorly defined. As other immune checkpoint inhibitors have transformed the management of difficult to treat cancers, such as melanoma, it is hoped that LAG-3 might have the same potential. This review will explore LAG-3 modulation as an anticancer therapy, highlighting recent clinical developments.

scholarly journals Lymphocyte Activation Gene 3 (LAG-3) Modulates the Ability of CD4 T-cells to Be Suppressed In Vivo

PLoS ONE ◽  
2014 ◽  
Vol 9 (11) ◽  
pp. e109080 ◽  
Author(s):  
Nicholas M. Durham ◽  
Christopher J. Nirschl ◽  
Christopher M. Jackson ◽  
Jimmy Elias ◽  
Christina M. Kochel ◽  
...  
Keyword(s):  
T Cells ◽  
Cd4 T Cells ◽  
Lymphocyte Activation ◽  
Lymphocyte Activation Gene

scholarly journals RIT2 reduces LRRK2 kinase activity and protects against alpha-synuclein neuropathology

2020 ◽  
Author(s):  
Julia Obergasteiger ◽  
Anne-Marie Castonguay ◽  
Giulia Frapporti ◽  
Evy Lobbestael ◽  
Veerle Baekelandt ◽  
...  
Keyword(s):  
Risk Factor ◽  
Substantia Nigra ◽  
Dopaminergic Neurons ◽  
Kinase Activity ◽  
Alpha Synuclein ◽  
The Novel ◽  
Lrrk2 Kinase ◽  
Novel Strategy ◽  
Lrrk2 Kinase Activity

AbstractIn Parkinson’s disease (PD) misfolded alpha-synuclein (aSyn) accumulates in the substantia nigra, where dopaminergic neurons are progressively lost. The mechanisms underlying aSyn pathology are still unclear but hypothesized to involve the autophagy lysosome pathways (ALP). LRRK2 mutations are a major cause of familial and sporadic PD, hyperactivate kinase activity and its pharmacological inhibition reduces pS129-aSyn inclusions. We observed selective downregulation of the novel PD risk factor RIT2 in G2019S-LRRK2 expressing cells. Here we studied whether RIT2 could modulate LRRK2 kinase activity. RIT2 overexpression in G2019S-LRRK2 cells rescued ALP abnormalities and diminished aSyn inclusions. In vivo, viral mediated overexpression of RIT2 operated neuroprotection against AAV-A53T-aSyn. Furthermore, RIT2 overexpression prevented the A53T-aSyn-dependent increase of LRRK2 kinase activity in vivo. Our data indicate that RIT2 inhibits overactive LRRK2 to ameliorate ALP impairment and counteract aSyn aggregation and related deficits. Targeting RIT2 could represent a novel strategy to combat neuropathology in familial and idiopathic PD.

scholarly journals Alpha-synuclein-induced mitochondrial dysfunction is mediated via a sirtuin 3-dependent pathway

2018 ◽  
Author(s):  
Jae-Hyeon Park ◽  
Marion Delenclos ◽  
Ayman H. Faroqi ◽  
Natasha N. DeMeo ◽  
Pamela J. McLean
Keyword(s):  
Parkinson Disease ◽  
Mitochondrial Dysfunction ◽  
Mitochondrial Function ◽  
Mitochondrial Dynamics ◽  
Lewy Body Disease ◽  
Camp Response Element Binding ◽  
Protective Role ◽  
Alpha Synuclein ◽  
Sirtuin 3

AbstractThe sirtuins are highly conserved nicotinamide adenine dinucleotide (NAD+)-dependent enzymes that play a broad role in cellular metabolism and aging. Mitochondrial sirtuin 3 (SIRT3) is downregulated in aging and age-associated diseases such as cancer and neuro-degeneration and plays a major role in maintaining mitochondrial function and preventing oxidative stress. Mitochondria dysfunction is central to the pathogenesis of Parkinson disease with mutations in mitochondrial-associated proteins such as PINK1 and parkin causing familial Parkinson disease. Here, we demonstrate that the presence of alpha-synuclein (αsyn) oligomers in mitochondria induce a corresponding decrease in mitochondrial SIRT3 activity and decreased mitochondrial biogenesis. We show that SIRT3 downregulation in the presence of αsyn accumulation is accompanied by increased phosphorylation of AMP-activated protein kinase (AMPK) and cAMP-response element binding protein (CREB), as well as increased phosphorylation of dynamin-related protein 1 (DRP1) and decreased levels of optic atrophy 1 (OPA1), which is indicative of impaired mitochondrial dynamics. Treatment with the AMPK agonist 5-aminoimidazole-4-carboxamide-1-β-d-ribofuranoside (AICAR) restores SIRT3 expression and activity and improves mitochondrial function by decreasing αsyn oligomer formation. The accumulation of αsyn oligomers in mitochondria corresponds with SIRT3 down-regulation not only in an experimental cellular model, but also in vivo in a rodent model of Parkinson disease, and importantly, in human post mortem brains with neuropathologically confirmed Lewy body disease (LBD). Taken together our findings suggest that pharmacologically increasing SIRT3 levels will counteract αsyn-induced mitochondrial dysfunction by normalizing mitochondrial bioenergetics. These data support a protective role for SIRT3 in Parkinson disease-associated pathways and reveals significant mechanistic insight into the interplay of SIRT3 and αsyn.

scholarly journals Targeting alpha synuclein and amyloid beta by a multifunctional, brain-penetrant dopamine D2/D3 agonist D-520: Potential therapeutic application in Parkinson’s disease with dementia

2019 ◽  
Vol 9 (1) ◽  
Author(s):  
Deepthi Yedlapudi ◽  
Liping Xu ◽  
Dan Luo ◽  
Gregory B. Marsh ◽  
Sokol V. Todi ◽  
...  
Keyword(s):  
Parkinson’S Disease ◽  
Parkinson's Disease ◽  
Amyloid Beta ◽  
Alpha Synuclein ◽  
Motor Dysfunction ◽  
Dopamine D2 ◽  
Potential Therapeutic Application ◽  
Aβ Aggregation

AbstractA significant number of people with Parkinson’s disease (PD) develop dementia in addition to cognitive dysfunction and are diagnosed as PD with dementia (PDD). This is characterized by cortical and limbic alpha synuclein (α-syn) accumulation, and high levels of diffuse amyloid beta (Aβ) plaques in the striatum and neocortical areas. In this regard, we evaluated the effect of a brain-penetrant, novel multifunctional dopamine D2/D3 agonist, D-520 on the inhibition of Aβ aggregation and disintegration of α-syn and Aβ aggregates in vitro using purified proteins and in a cell culture model that produces intracellular Aβ-induced toxicity. We further evaluated the effect of D-520 in a Drosophila model of Aβ1-42 toxicity. We report that D-520 inhibits the formation of Aβ aggregates in vitro and promotes the disaggregation of both α-syn and Aβ aggregates. Finally, in an in vivo Drosophila model of Aβ1-42 dependent toxicity, D-520 exhibited efficacy by rescuing fly eyes from retinal degeneration caused by Aβ toxicity. Our data indicate the potential therapeutic applicability of D-520 in addressing motor dysfunction and neuroprotection in PD and PDD, as well as attenuating dementia in people with PDD.

scholarly journals Mitochondrial alpha-synuclein accumulation impairs complex I function in dopaminergic neurons and results in increased mitophagy in vivo

2010 ◽  
Vol 486 (3) ◽  
pp. 235-239 ◽  
Author(s):  
Shankar J. Chinta ◽  
Jyothi K. Mallajosyula ◽  
Anand Rane ◽  
Julie K. Andersen
Keyword(s):  
Dopaminergic Neurons ◽  
Complex I ◽  
Alpha Synuclein

The Localization and Functional Contribution of Striatal Aromatic L-Amino Acid Decarboxylase to L-3,4-Dihydroxyphenylalanine Decarboxylation in Rodent Parkinsonian Models

2000 ◽  
Vol 9 (5) ◽  
pp. 567-576 ◽  
Author(s):  
Ken Nakamura ◽  
Maqbool Ahmed ◽  
Eliav Barr ◽  
Jeffrey M. Leiden ◽  
Un Jung Kang
Keyword(s):  
Amino Acid ◽  
Dopaminergic Neurons ◽  
Primary Source ◽  
Therapeutic Strategies ◽  
Acid Decarboxylase ◽  
Striatal Neurons ◽  
Amino Acid Decarboxylase ◽  
Cellular Transplantation

L-3,4-Dihydroxyphenylalanine (L-dopa) is the mainstay of therapy for patients with Parkinson's disease (PD), and mediates its primary effects through conversion into dopamine by aromatic L-amino acid decarboxylase (AADC). Given the loss of AADC-containing nigrostriatal dopaminergic neurons in PD, however, the location of residual AADC that converts L-dopa into dopamine remains controversial. The first objective of this study was to establish the presence of AADC expression in striatal neurons and glia using reverse transcriptase and PCR. Transcripts for the neuronal but not nonneuronal forms of AADC were detected in striatal tissue, cultured striatal neurons, and glia. We then examined whether this striatal AADC expression represents a physiologically significant source of dopamine production. No dopamine release was detected following incubation of striatal cultures with L-dopa or transduction with adenovirus expressing tyrosine hydroxylase. Our data establish the presence of AADC expression in the striatum both in vivo and in vitro, but suggest that striatal components do not represent a primary source of L-dopa decarboxylation following nigrostriatal denervation in rats. Understanding the source and localization of AADC is important in understanding the complications of L-dopa therapy and in designing rational therapeutic strategies for PD, including cellular transplantation and gene therapy.

scholarly journals Neuronal NADPH oxidase in Parkinson disease pathogenesis

2021 ◽  
Author(s):  
Matthew T Keeney ◽  
Eric K Hoffman ◽  
Kyle Farmer ◽  
Christopher R Bodle ◽  
Marco Fazzari ◽  
...  
Keyword(s):  
Oxidative Stress ◽  
Nadph Oxidase ◽  
Parkinson Disease ◽  
Alpha Synuclein ◽  
Dopamine Neurons ◽  
Proximity Ligation Assay ◽  
Post Translational Modification ◽  
Highly Active ◽  
Downstream Effects

Mitochondrial dysfunction and oxidative stress are strongly implicated in the pathogenesis of Parkinson disease (PD) and there is evidence that mitochondrially-generated superoxide can activate NADPH oxidase 2 (NOX2), which is a major enzymatic generator of superoxide. Although NOX2 has been examined in the context of PD, previous studies have focused on microglial function; the role of neuronal NOX2 in PD pathogenesis remains to be defined. Here we devised and validated a proximity ligation assay for NOX2 activity and demonstrated that in human PD and 2 models thereof, neuronal NOX2 is highly active in substantia nigra dopamine neurons. Further, NOX2 activity is responsible for accumulation, post-translational modification and oligomerization of alpha-synuclein as well as activation of leucine-rich repeat kinase 2 (LRRK2). Administration of a brain-penetrant, specific NOX2 inhibitor prevented NOX2 activation and its downstream effects in vivo in a rat model of PD. We conclude that neuronal NOX2 is a major contributor to oxidative stress in PD, to alpha-synuclein pathology and to LRRK2 activation in idiopathic PD. In this context, NOX2 inhibitors hold potential as a disease-modifying therapy in PD.

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