Your browser doesn't support javascript.
loading
Mostrar: 20 | 50 | 100
Resultados 1 - 20 de 10.536
Filtrar
Mais filtros

Intervalo de ano de publicação
1.
Annu Rev Biochem ; 93(1): 261-287, 2024 Aug.
Artigo em Inglês | MEDLINE | ID: mdl-38621236

RESUMO

Activating mutations in leucine-rich repeat kinase 2 (LRRK2) represent the most common cause of monogenic Parkinson's disease. LRRK2 is a large multidomain protein kinase that phosphorylates a specific subset of the ∼65 human Rab GTPases, which are master regulators of the secretory and endocytic pathways. After phosphorylation by LRRK2, Rabs lose the capacity to bind cognate effector proteins and guanine nucleotide exchange factors. Moreover, the phosphorylated Rabs cannot interact with their cognate prenyl-binding retrieval proteins (also known as guanine nucleotide dissociation inhibitors) and, thus, they become trapped on membrane surfaces. Instead, they gain the capacity to bind phospho-Rab-specific effector proteins, such as RILPL1, with resulting pathological consequences. Rab proteins also act upstream of LRRK2 by controlling its activation and recruitment onto membranes. LRRK2 signaling is counteracted by the phosphoprotein phosphatase PPM1H, which selectively dephosphorylates phospho-Rab proteins. We present here our current understanding of the structure, biochemical properties, and cell biology of LRRK2 and its related paralog LRRK1 and discuss how this information guides the generation of LRRK2 inhibitors for the potential benefit of patients.


Assuntos
Serina-Treonina Proteína Quinase-2 com Repetições Ricas em Leucina , Doença de Parkinson , Proteínas rab de Ligação ao GTP , Humanos , Serina-Treonina Proteína Quinase-2 com Repetições Ricas em Leucina/metabolismo , Serina-Treonina Proteína Quinase-2 com Repetições Ricas em Leucina/genética , Serina-Treonina Proteína Quinase-2 com Repetições Ricas em Leucina/química , Fosforilação , Doença de Parkinson/metabolismo , Doença de Parkinson/genética , Doença de Parkinson/patologia , Proteínas rab de Ligação ao GTP/metabolismo , Proteínas rab de Ligação ao GTP/genética , Proteínas rab de Ligação ao GTP/química , Animais , Transdução de Sinais , Mutação , Proteínas Serina-Treonina Quinases/metabolismo , Proteínas Serina-Treonina Quinases/genética , Proteínas Serina-Treonina Quinases/química , Ligação Proteica , Fosfoproteínas Fosfatases/metabolismo , Fosfoproteínas Fosfatases/genética , Fosfoproteínas Fosfatases/química
2.
Annu Rev Biochem ; 92: 435-464, 2023 06 20.
Artigo em Inglês | MEDLINE | ID: mdl-37018845

RESUMO

The polyamines putrescine, spermidine, and spermine are abundant polycations of vital importance in mammalian cells. Their cellular levels are tightly regulated by degradation and synthesis, as well as by uptake and export. Here, we discuss the delicate balance between the neuroprotective and neurotoxic effects of polyamines in the context of Parkinson's disease (PD). Polyamine levels decline with aging and are altered in patients with PD, whereas recent mechanistic studies on ATP13A2 (PARK9) demonstrated a driving role of a disturbed polyamine homeostasis in PD. Polyamines affect pathways in PD pathogenesis, such as α-synuclein aggregation, and influence PD-related processes like autophagy, heavy metal toxicity, oxidative stress, neuroinflammation, and lysosomal/mitochondrial dysfunction. We formulate outstanding research questions regarding the role of polyamines in PD, their potential as PD biomarkers, and possible therapeutic strategies for PD targeting polyamine homeostasis.


Assuntos
Doença de Parkinson , Transtornos Parkinsonianos , Animais , Humanos , Doença de Parkinson/genética , Doença de Parkinson/metabolismo , Doença de Parkinson/patologia , Poliaminas/metabolismo , Neuroproteção , Espermidina/metabolismo , Mamíferos/metabolismo
3.
Cell ; 182(6): 1508-1518.e16, 2020 09 17.
Artigo em Inglês | MEDLINE | ID: mdl-32783917

RESUMO

Mutations in leucine-rich repeat kinase 2 (LRRK2) are the most frequent cause of familial Parkinson's disease. LRRK2 is a multi-domain protein containing a kinase and GTPase. Using correlative light and electron microscopy, in situ cryo-electron tomography, and subtomogram analysis, we reveal a 14-Å structure of LRRK2 bearing a pathogenic mutation that oligomerizes as a right-handed double helix around microtubules, which are left-handed. Using integrative modeling, we determine the architecture of LRRK2, showing that the GTPase and kinase are in close proximity, with the GTPase closer to the microtubule surface, whereas the kinase is exposed to the cytoplasm. We identify two oligomerization interfaces mediated by non-catalytic domains. Mutation of one of these abolishes LRRK2 microtubule-association. Our work demonstrates the power of cryo-electron tomography to generate models of previously unsolved structures in their cellular environment.


Assuntos
Microscopia Crioeletrônica/métodos , Tomografia com Microscopia Eletrônica/métodos , Serina-Treonina Proteína Quinase-2 com Repetições Ricas em Leucina/química , Microtúbulos/metabolismo , Doença de Parkinson/metabolismo , Citoplasma/metabolismo , GTP Fosfo-Hidrolases/química , GTP Fosfo-Hidrolases/metabolismo , Células HEK293 , Humanos , Microscopia Eletrônica de Transmissão , Microtúbulos/química , Modelos Químicos , Mutação , Doença de Parkinson/genética , Doença de Parkinson/patologia , Fosfotransferases/química , Fosfotransferases/metabolismo , Domínios Proteicos , Repetições WD40
4.
Annu Rev Biochem ; 86: 21-26, 2017 06 20.
Artigo em Inglês | MEDLINE | ID: mdl-28441058

RESUMO

The majority of protein molecules must fold into defined three-dimensional structures to acquire functional activity. However, protein chains can adopt a multitude of conformational states, and their biologically active conformation is often only marginally stable. Metastable proteins tend to populate misfolded species that are prone to forming toxic aggregates, including soluble oligomers and fibrillar amyloid deposits, which are linked with neurodegeneration in Alzheimer and Parkinson disease, and many other pathologies. To prevent or regulate protein aggregation, all cells contain an extensive protein homeostasis (or proteostasis) network comprising molecular chaperones and other factors. These defense systems tend to decline during aging, facilitating the manifestation of aggregate deposition diseases. This volume of the Annual Review of Biochemistry contains a set of three articles addressing our current understanding of the structures of pathological protein aggregates and their associated disease mechanisms. These articles also discuss recent insights into the strategies cells have evolved to neutralize toxic aggregates by sequestering them in specific cellular locations.


Assuntos
Envelhecimento/metabolismo , Doença de Alzheimer/metabolismo , Doença de Parkinson/metabolismo , Agregação Patológica de Proteínas/metabolismo , Deficiências na Proteostase/metabolismo , Envelhecimento/genética , Envelhecimento/patologia , Doença de Alzheimer/genética , Doença de Alzheimer/patologia , Amiloide/química , Amiloide/genética , Amiloide/metabolismo , Regulação da Expressão Gênica , Humanos , Chaperonas Moleculares/genética , Chaperonas Moleculares/metabolismo , Doença de Parkinson/genética , Doença de Parkinson/patologia , Agregação Patológica de Proteínas/genética , Agregação Patológica de Proteínas/patologia , Conformação Proteica , Dobramento de Proteína , Deficiências na Proteostase/genética , Deficiências na Proteostase/patologia
5.
Annu Rev Biochem ; 86: 27-68, 2017 06 20.
Artigo em Inglês | MEDLINE | ID: mdl-28498720

RESUMO

Peptides and proteins have been found to possess an inherent tendency to convert from their native functional states into intractable amyloid aggregates. This phenomenon is associated with a range of increasingly common human disorders, including Alzheimer and Parkinson diseases, type II diabetes, and a number of systemic amyloidoses. In this review, we describe this field of science with particular reference to the advances that have been made over the last decade in our understanding of its fundamental nature and consequences. We list the proteins that are known to be deposited as amyloid or other types of aggregates in human tissues and the disorders with which they are associated, as well as the proteins that exploit the amyloid motif to play specific functional roles in humans. In addition, we summarize the genetic factors that have provided insight into the mechanisms of disease onset. We describe recent advances in our knowledge of the structures of amyloid fibrils and their oligomeric precursors and of the mechanisms by which they are formed and proliferate to generate cellular dysfunction. We show evidence that a complex proteostasis network actively combats protein aggregation and that such an efficient system can fail in some circumstances and give rise to disease. Finally, we anticipate the development of novel therapeutic strategies with which to prevent or treat these highly debilitating and currently incurable conditions.


Assuntos
Doença de Alzheimer/história , Amiloide/química , Amiloidose/história , Diabetes Mellitus Tipo 2/história , Doença de Parkinson/história , Deficiências na Proteostase/história , Doença de Alzheimer/tratamento farmacológico , Doença de Alzheimer/metabolismo , Doença de Alzheimer/patologia , Amiloide/genética , Amiloide/metabolismo , Amiloidose/tratamento farmacológico , Amiloidose/metabolismo , Amiloidose/patologia , Diabetes Mellitus Tipo 2/tratamento farmacológico , Diabetes Mellitus Tipo 2/metabolismo , Diabetes Mellitus Tipo 2/patologia , Drogas em Investigação , Regulação da Expressão Gênica , História do Século XXI , Humanos , Amiloidose de Cadeia Leve de Imunoglobulina , Chaperonas Moleculares/genética , Chaperonas Moleculares/metabolismo , Terapia de Alvo Molecular , Doença de Parkinson/tratamento farmacológico , Doença de Parkinson/metabolismo , Doença de Parkinson/patologia , Agregação Patológica de Proteínas/história , Agregação Patológica de Proteínas/metabolismo , Agregação Patológica de Proteínas/patologia , Agregação Patológica de Proteínas/prevenção & controle , Conformação Proteica , Dobramento de Proteína , Deficiências na Proteostase/tratamento farmacológico , Deficiências na Proteostase/metabolismo , Deficiências na Proteostase/patologia , Deficiências na Proteostase/prevenção & controle
6.
Annu Rev Cell Dev Biol ; 34: 545-568, 2018 10 06.
Artigo em Inglês | MEDLINE | ID: mdl-30044648

RESUMO

Most neurodegenerative diseases are characterized by the accumulation of protein aggregates, some of which are toxic to cells. Mounting evidence demonstrates that in several diseases, protein aggregates can pass from neuron to neuron along connected networks, although the role of this spreading phenomenon in disease pathogenesis is not completely understood. Here we briefly review the molecular and histopathological features of protein aggregation in neurodegenerative disease, we summarize the evidence for release of proteins from donor cells into the extracellular space, and we highlight some other mechanisms by which protein aggregates might be transmitted to recipient cells. We also discuss the evidence that supports a role for spreading of protein aggregates in neurodegenerative disease pathogenesis and some limitations of this model. Finally, we consider potential therapeutic strategies to target spreading of protein aggregates in the treatment of neurodegenerative diseases.


Assuntos
Doenças Neurodegenerativas/genética , Neurônios/metabolismo , Agregados Proteicos/genética , Agregação Patológica de Proteínas/genética , Doença de Alzheimer/genética , Doença de Alzheimer/patologia , Esclerose Lateral Amiotrófica/genética , Esclerose Lateral Amiotrófica/patologia , Encefalopatia Traumática Crônica/genética , Encefalopatia Traumática Crônica/patologia , Demência Frontotemporal/genética , Demência Frontotemporal/patologia , Humanos , Doença de Huntington/genética , Doença de Huntington/patologia , Doenças Neurodegenerativas/classificação , Doenças Neurodegenerativas/patologia , Neurônios/patologia , Doença de Parkinson/genética , Doença de Parkinson/patologia , Doenças Priônicas/genética , Doenças Priônicas/patologia , Agregação Patológica de Proteínas/patologia
7.
Nat Rev Mol Cell Biol ; 20(7): 421-435, 2019 07.
Artigo em Inglês | MEDLINE | ID: mdl-30733602

RESUMO

Ageing is a major risk factor for the development of many diseases, prominently including neurodegenerative disorders such as Alzheimer disease and Parkinson disease. A hallmark of many age-related diseases is the dysfunction in protein homeostasis (proteostasis), leading to the accumulation of protein aggregates. In healthy cells, a complex proteostasis network, comprising molecular chaperones and proteolytic machineries and their regulators, operates to ensure the maintenance of proteostasis. These factors coordinate protein synthesis with polypeptide folding, the conservation of protein conformation and protein degradation. However, sustaining proteome balance is a challenging task in the face of various external and endogenous stresses that accumulate during ageing. These stresses lead to the decline of proteostasis network capacity and proteome integrity. The resulting accumulation of misfolded and aggregated proteins affects, in particular, postmitotic cell types such as neurons, manifesting in disease. Recent analyses of proteome-wide changes that occur during ageing inform strategies to improve proteostasis. The possibilities of pharmacological augmentation of the capacity of proteostasis networks hold great promise for delaying the onset of age-related pathologies associated with proteome deterioration and for extending healthspan.


Assuntos
Doença de Alzheimer/metabolismo , Chaperonas Moleculares/metabolismo , Doença de Parkinson/metabolismo , Dobramento de Proteína , Proteólise , Proteostase , Doença de Alzheimer/genética , Doença de Alzheimer/patologia , Animais , Humanos , Chaperonas Moleculares/genética , Doença de Parkinson/genética , Doença de Parkinson/patologia
8.
Cell ; 167(6): 1469-1480.e12, 2016 Dec 01.
Artigo em Inglês | MEDLINE | ID: mdl-27912057

RESUMO

The intestinal microbiota influence neurodevelopment, modulate behavior, and contribute to neurological disorders. However, a functional link between gut bacteria and neurodegenerative diseases remains unexplored. Synucleinopathies are characterized by aggregation of the protein α-synuclein (αSyn), often resulting in motor dysfunction as exemplified by Parkinson's disease (PD). Using mice that overexpress αSyn, we report herein that gut microbiota are required for motor deficits, microglia activation, and αSyn pathology. Antibiotic treatment ameliorates, while microbial re-colonization promotes, pathophysiology in adult animals, suggesting that postnatal signaling between the gut and the brain modulates disease. Indeed, oral administration of specific microbial metabolites to germ-free mice promotes neuroinflammation and motor symptoms. Remarkably, colonization of αSyn-overexpressing mice with microbiota from PD-affected patients enhances physical impairments compared to microbiota transplants from healthy human donors. These findings reveal that gut bacteria regulate movement disorders in mice and suggest that alterations in the human microbiome represent a risk factor for PD.


Assuntos
Doença de Parkinson/microbiologia , Doença de Parkinson/patologia , Animais , Encéfalo/patologia , Disbiose/patologia , Ácidos Graxos/metabolismo , Microbioma Gastrointestinal , Trato Gastrointestinal/microbiologia , Trato Gastrointestinal/fisiopatologia , Humanos , Inflamação/metabolismo , Inflamação/microbiologia , Inflamação/patologia , Camundongos , Microglia/patologia , Doença de Parkinson/metabolismo , Doença de Parkinson/fisiopatologia , alfa-Sinucleína/metabolismo
9.
Cell ; 166(2): 314-327, 2016 Jul 14.
Artigo em Inglês | MEDLINE | ID: mdl-27345367

RESUMO

Antigen presentation is essential for establishing immune tolerance and for immune responses against infectious disease and cancer. Although antigen presentation can be mediated by autophagy, here we demonstrate a pathway for mitochondrial antigen presentation (MitAP) that relies on the generation and trafficking of mitochondrial-derived vesicles (MDVs) rather than on autophagy/mitophagy. We find that PINK1 and Parkin, two mitochondrial proteins linked to Parkinson's disease (PD), actively inhibit MDV formation and MitAP. In absence of PINK1 or Parkin, inflammatory conditions trigger MitAP in immune cells, both in vitro and in vivo. MitAP and the formation of MDVs require Rab9 and Sorting nexin 9, whose recruitment to mitochondria is inhibited by Parkin. The identification of PINK1 and Parkin as suppressors of an immune-response-eliciting pathway provoked by inflammation suggests new insights into PD pathology.


Assuntos
Apresentação de Antígeno , Mitocôndrias/imunologia , Doença de Parkinson/imunologia , Proteínas Quinases/metabolismo , Ubiquitina-Proteína Ligases/metabolismo , Animais , Células Dendríticas/patologia , Modelos Animais de Doenças , Inflamação/metabolismo , Macrófagos/patologia , Camundongos , Camundongos Endogâmicos BALB C , Camundongos Endogâmicos C57BL , Doença de Parkinson/patologia , Proteínas Quinases/genética , Vesículas Transportadoras/metabolismo , Ubiquitina-Proteína Ligases/genética
10.
Cell ; 163(2): 324-39, 2015 Oct 08.
Artigo em Inglês | MEDLINE | ID: mdl-26451483

RESUMO

Neurodegenerative diseases have been linked to inflammation, but whether altered immunomodulation plays a causative role in neurodegeneration is not clear. We show that lack of cytokine interferon-ß (IFN-ß) signaling causes spontaneous neurodegeneration in the absence of neurodegenerative disease-causing mutant proteins. Mice lacking Ifnb function exhibited motor and cognitive learning impairments with accompanying α-synuclein-containing Lewy bodies in the brain, as well as a reduction in dopaminergic neurons and defective dopamine signaling in the nigrostriatal region. Lack of IFN-ß signaling caused defects in neuronal autophagy prior to α-synucleinopathy, which was associated with accumulation of senescent mitochondria. Recombinant IFN-ß promoted neurite growth and branching, autophagy flux, and α-synuclein degradation in neurons. In addition, lentiviral IFN-ß overexpression prevented dopaminergic neuron loss in a familial Parkinson's disease model. These results indicate a protective role for IFN-ß in neuronal homeostasis and validate Ifnb mutant mice as a model for sporadic Lewy body and Parkinson's disease dementia.


Assuntos
Interferon beta/metabolismo , Neurônios/metabolismo , Receptor de Interferon alfa e beta/metabolismo , Animais , Autofagia , Modelos Animais de Doenças , Terapia Genética , Interferon beta/genética , Interferon beta/uso terapêutico , Doença por Corpos de Lewy/metabolismo , Doença por Corpos de Lewy/patologia , Camundongos , Camundongos Endogâmicos C57BL , Doença de Parkinson/genética , Doença de Parkinson/metabolismo , Doença de Parkinson/patologia , Doença de Parkinson/terapia , Receptor de Interferon alfa e beta/genética , Transdução de Sinais , Transcriptoma , alfa-Sinucleína/metabolismo
11.
Nat Rev Neurosci ; 25(6): 393-413, 2024 Jun.
Artigo em Inglês | MEDLINE | ID: mdl-38600347

RESUMO

Parkinson disease (PD) is a neurodegenerative disorder marked by the preferential dysfunction and death of dopaminergic neurons in the substantia nigra. The onset and progression of PD is influenced by a diversity of genetic variants, many of which lack functional characterization. To identify the most high-yield targets for therapeutic intervention, it is important to consider the core cellular compartments and functional pathways upon which the varied forms of pathogenic dysfunction may converge. Here, we review several key PD-linked proteins and pathways, focusing on the mechanisms of their potential convergence in disease pathogenesis. These dysfunctions primarily localize to a subset of subcellular compartments, including mitochondria, lysosomes and synapses. We discuss how these pathogenic mechanisms that originate in different cellular compartments may coordinately lead to cellular dysfunction and neurodegeneration in PD.


Assuntos
Doença de Parkinson , Doença de Parkinson/genética , Doença de Parkinson/patologia , Doença de Parkinson/metabolismo , Humanos , Animais , Mitocôndrias/genética , Mitocôndrias/metabolismo , Neurônios Dopaminérgicos/patologia , Neurônios Dopaminérgicos/metabolismo , Lisossomos/metabolismo , Lisossomos/genética , Sinapses/patologia , Sinapses/genética , Sinapses/metabolismo
12.
Cell ; 157(2): 472-485, 2014 Apr 10.
Artigo em Inglês | MEDLINE | ID: mdl-24725412

RESUMO

Mutations in leucine-rich repeat kinase 2 (LRRK2) are a common cause of familial and sporadic Parkinson's disease (PD). Elevated LRRK2 kinase activity and neurodegeneration are linked, but the phosphosubstrate that connects LRRK2 kinase activity to neurodegeneration is not known. Here, we show that ribosomal protein s15 is a key pathogenic LRRK2 substrate in Drosophila and human neuron PD models. Phosphodeficient s15 carrying a threonine 136 to alanine substitution rescues dopamine neuron degeneration and age-related locomotor deficits in G2019S LRRK2 transgenic Drosophila and substantially reduces G2019S LRRK2-mediated neurite loss and cell death in human dopamine and cortical neurons. Remarkably, pathogenic LRRK2 stimulates both cap-dependent and cap-independent mRNA translation and induces a bulk increase in protein synthesis in Drosophila, which can be prevented by phosphodeficient T136A s15. These results reveal a novel mechanism of PD pathogenesis linked to elevated LRRK2 kinase activity and aberrant protein synthesis in vivo.


Assuntos
Neurônios/metabolismo , Doença de Parkinson/metabolismo , Proteínas Serina-Treonina Quinases/metabolismo , Proteínas Ribossômicas/metabolismo , Sequência de Aminoácidos , Animais , Drosophila melanogaster , Humanos , Serina-Treonina Proteína Quinase-2 com Repetições Ricas em Leucina , Dados de Sequência Molecular , Neurônios/patologia , Doença de Parkinson/patologia , Proteínas Ribossômicas/química
13.
Cell ; 156(1-2): 170-82, 2014 Jan 16.
Artigo em Inglês | MEDLINE | ID: mdl-24439375

RESUMO

There are no therapies that reverse the proteotoxic misfolding events that underpin fatal neurodegenerative diseases, including amyotrophic lateral sclerosis (ALS) and Parkinson's disease (PD). Hsp104, a conserved hexameric AAA+ protein from yeast, solubilizes disordered aggregates and amyloid but has no metazoan homolog and only limited activity against human neurodegenerative disease proteins. Here, we reprogram Hsp104 to rescue TDP-43, FUS, and α-synuclein proteotoxicity by mutating single residues in helix 1, 2, or 3 of the middle domain or the small domain of nucleotide-binding domain 1. Potentiated Hsp104 variants enhance aggregate dissolution, restore proper protein localization, suppress proteotoxicity, and in a C. elegans PD model attenuate dopaminergic neurodegeneration. Potentiating mutations reconfigure how Hsp104 subunits collaborate, desensitize Hsp104 to inhibition, obviate any requirement for Hsp70, and enhance ATPase, translocation, and unfoldase activity. Our work establishes that disease-associated aggregates and amyloid are tractable targets and that enhanced disaggregases can restore proteostasis and mitigate neurodegeneration.


Assuntos
Caenorhabditis elegans , Modelos Animais de Doenças , Proteínas de Choque Térmico/genética , Proteínas de Choque Térmico/metabolismo , Proteínas de Saccharomyces cerevisiae/genética , Proteínas de Saccharomyces cerevisiae/metabolismo , Animais , Animais Geneticamente Modificados , Proteínas de Ligação a DNA/metabolismo , Proteínas de Choque Térmico/química , Humanos , Modelos Moleculares , Mutagênese , Neurônios/citologia , Neurônios/patologia , Doença de Parkinson/metabolismo , Doença de Parkinson/patologia , Doença de Parkinson/terapia , Dobramento de Proteína , Estrutura Terciária de Proteína , Deficiências na Proteostase/metabolismo , Deficiências na Proteostase/patologia , Deficiências na Proteostase/terapia , Proteína FUS de Ligação a RNA/metabolismo , Proteínas de Saccharomyces cerevisiae/química , alfa-Sinucleína/metabolismo
14.
Nature ; 619(7970): 606-615, 2023 Jul.
Artigo em Inglês | MEDLINE | ID: mdl-37438521

RESUMO

The specific loss of midbrain dopamine neurons (mDANs) causes major motor dysfunction in Parkinson's disease, which makes cell replacement a promising therapeutic approach1-4. However, poor survival of grafted mDANs remains an obstacle to successful clinical outcomes5-8. Here we show that the surgical procedure itself (referred to here as 'needle trauma') triggers a profound host response that is characterized by acute neuroinflammation, robust infiltration of peripheral immune cells and brain cell death. When midbrain dopamine (mDA) cells derived from human induced pluripotent stem (iPS) cells were transplanted into the rodent striatum, less than 10% of implanted tyrosine hydroxylase (TH)+ mDANs survived at two weeks after transplantation. By contrast, TH- grafted cells mostly survived. Notably, transplantation of autologous regulatory T (Treg) cells greatly modified the response to needle trauma, suppressing acute neuroinflammation and immune cell infiltration. Furthermore, intra-striatal co-transplantation of Treg cells and human-iPS-cell-derived mDA cells significantly protected grafted mDANs from needle-trauma-associated death and improved therapeutic outcomes in rodent models of Parkinson's disease with 6-hydroxydopamine lesions. Co-transplantation with Treg cells also suppressed the undesirable proliferation of TH- grafted cells, resulting in more compact grafts with a higher proportion and higher absolute numbers of TH+ neurons. Together, these data emphasize the importance of the initial inflammatory response to surgical injury in the differential survival of cellular components of the graft, and suggest that co-transplanting autologous Treg cells effectively reduces the needle-trauma-induced death of mDANs, providing a potential strategy to achieve better clinical outcomes for cell therapy in Parkinson's disease.


Assuntos
Terapia Baseada em Transplante de Células e Tecidos , Neurônios Dopaminérgicos , Sobrevivência de Enxerto , Doenças Neuroinflamatórias , Doença de Parkinson , Linfócitos T Reguladores , Tirosina 3-Mono-Oxigenase , Humanos , Dopamina/análogos & derivados , Dopamina/metabolismo , Neurônios Dopaminérgicos/imunologia , Neurônios Dopaminérgicos/metabolismo , Neurônios Dopaminérgicos/transplante , Mesencéfalo/patologia , Doenças Neuroinflamatórias/etiologia , Doenças Neuroinflamatórias/imunologia , Doenças Neuroinflamatórias/prevenção & controle , Doenças Neuroinflamatórias/terapia , Doença de Parkinson/complicações , Doença de Parkinson/patologia , Doença de Parkinson/cirurgia , Doença de Parkinson/terapia , Tirosina 3-Mono-Oxigenase/deficiência , Tirosina 3-Mono-Oxigenase/metabolismo , Linfócitos T Reguladores/imunologia , Linfócitos T Reguladores/transplante , Terapia Baseada em Transplante de Células e Tecidos/métodos , Animais , Camundongos , Ratos , Oxidopamina/metabolismo , Sobrevivência de Enxerto/imunologia , Morte Celular , Células-Tronco Pluripotentes Induzidas/citologia , Células-Tronco Pluripotentes Induzidas/imunologia , Células-Tronco Pluripotentes Induzidas/metabolismo , Células-Tronco Pluripotentes Induzidas/transplante , Neostriado/metabolismo , Fatores de Tempo , Proliferação de Células , Resultado do Tratamento
15.
Cell ; 154(4): 716-8, 2013 Aug 15.
Artigo em Inglês | MEDLINE | ID: mdl-23953104

RESUMO

Pharmacologic agents capable of increasing kinase function would be useful for treating diseases associated with reduced kinase activity, such as inherited forms of Parkinson's disease. In this issue, Hertz et al. report an innovative approach for activating the Parkinson's-associated kinase PINK1 in cells with an ATP-derived neo-substrate.


Assuntos
Mitocôndrias/metabolismo , Doença de Parkinson/patologia , Proteínas Quinases/genética , Proteínas Quinases/metabolismo , Animais , Humanos
16.
Cell ; 154(1): 103-17, 2013 Jul 03.
Artigo em Inglês | MEDLINE | ID: mdl-23827677

RESUMO

Many neurodegenerative diseases are characterized by the accumulation of insoluble protein aggregates, including neurofibrillary tangles comprised of tau in Alzheimer's disease and Lewy bodies composed of α-synuclein in Parkinson's disease. Moreover, different pathological proteins frequently codeposit in disease brains. To test whether aggregated α-synuclein can directly cross-seed tau fibrillization, we administered preformed α-synuclein fibrils assembled from recombinant protein to primary neurons and transgenic mice. Remarkably, we discovered two distinct strains of synthetic α-synuclein fibrils that demonstrated striking differences in the efficiency of cross-seeding tau aggregation, both in neuron cultures and in vivo. Proteinase K digestion revealed conformational differences between the two synthetic α-synuclein strains and also between sarkosyl-insoluble α-synuclein extracted from two subgroups of Parkinson's disease brains. We speculate that distinct strains of pathological α-synuclein likely exist in neurodegenerative disease brains and may underlie the tremendous heterogeneity of synucleinopathies.


Assuntos
Neurônios/metabolismo , Doença de Parkinson/patologia , alfa-Sinucleína/metabolismo , Proteínas tau/metabolismo , Amiloide/química , Amiloide/metabolismo , Animais , Células Cultivadas , Embrião de Mamíferos/metabolismo , Humanos , Masculino , Camundongos , Camundongos Transgênicos , Doença de Parkinson/metabolismo , Proteínas Recombinantes/metabolismo , alfa-Sinucleína/química
17.
Cell ; 155(6): 1351-64, 2013 Dec 05.
Artigo em Inglês | MEDLINE | ID: mdl-24290359

RESUMO

Parkinson's disease (PD) is characterized by loss of A9 dopaminergic (DA) neurons in the substantia nigra pars compacta (SNpc). An association has been reported between PD and exposure to mitochondrial toxins, including environmental pesticides paraquat, maneb, and rotenone. Here, using a robust, patient-derived stem cell model of PD allowing comparison of A53T α-synuclein (α-syn) mutant cells and isogenic mutation-corrected controls, we identify mitochondrial toxin-induced perturbations in A53T α-syn A9 DA neurons (hNs). We report a pathway whereby basal and toxin-induced nitrosative/oxidative stress results in S-nitrosylation of transcription factor MEF2C in A53T hNs compared to corrected controls. This redox reaction inhibits the MEF2C-PGC1α transcriptional network, contributing to mitochondrial dysfunction and apoptotic cell death. Our data provide mechanistic insight into gene-environmental interaction (GxE) in the pathogenesis of PD. Furthermore, using small-molecule high-throughput screening, we identify the MEF2C-PGC1α pathway as a therapeutic target to combat PD.


Assuntos
Interação Gene-Ambiente , Mitocôndrias/efeitos dos fármacos , Paraquat/toxicidade , Doença de Parkinson/genética , Doença de Parkinson/patologia , Humanos , Células-Tronco Pluripotentes Induzidas/metabolismo , Fatores de Transcrição MEF2 , Mutação/efeitos dos fármacos , Neurônios/metabolismo , Estresse Oxidativo , Doença de Parkinson/metabolismo , Coativador 1-alfa do Receptor gama Ativado por Proliferador de Peroxissomo , Espécies Reativas de Nitrogênio/metabolismo , Substância Negra/metabolismo , Fatores de Transcrição/metabolismo , Transcrição Gênica , alfa-Sinucleína/genética , alfa-Sinucleína/metabolismo
18.
Cell ; 154(4): 737-47, 2013 Aug 15.
Artigo em Inglês | MEDLINE | ID: mdl-23953109

RESUMO

Mitochondria have long been implicated in the pathogenesis of Parkinson's disease (PD). Mutations in the mitochondrial kinase PINK1 that reduce kinase activity are associated with mitochondrial defects and result in an autosomal-recessive form of early-onset PD. Therapeutic approaches for enhancing the activity of PINK1 have not been considered because no allosteric regulatory sites for PINK1 are known. Here, we show that an alternative strategy, a neo-substrate approach involving the ATP analog kinetin triphosphate (KTP), can be used to increase the activity of both PD-related mutant PINK1(G309D) and PINK1(WT). Moreover, we show that application of the KTP precursor kinetin to cells results in biologically significant increases in PINK1 activity, manifest as higher levels of Parkin recruitment to depolarized mitochondria, reduced mitochondrial motility in axons, and lower levels of apoptosis. Discovery of neo-substrates for kinases could provide a heretofore-unappreciated modality for regulating kinase activity.


Assuntos
Mitocôndrias/metabolismo , Doença de Parkinson/patologia , Proteínas Quinases/genética , Proteínas Quinases/metabolismo , Trifosfato de Adenosina/análogos & derivados , Sequência de Aminoácidos , Animais , Apoptose , Axônios/metabolismo , Linhagem Celular , Células Cultivadas , Hipocampo/citologia , Hipocampo/metabolismo , Humanos , Cinetina/metabolismo , Camundongos , Camundongos Endogâmicos C57BL , Dados de Sequência Molecular , Neurônios/citologia , Neurônios/metabolismo , Doença de Parkinson/enzimologia , Doença de Parkinson/genética , Fosforilação , Proteínas Quinases/química , Ratos , Alinhamento de Sequência , Ubiquitina-Proteína Ligases/metabolismo , Proteína bcl-X/metabolismo
19.
Nature ; 610(7933): 791-795, 2022 10.
Artigo em Inglês | MEDLINE | ID: mdl-36108674

RESUMO

Parkinson's disease (PD) is the most common movement disorder, with resting tremor, rigidity, bradykinesia and postural instability being major symptoms1. Neuropathologically, it is characterized by the presence of abundant filamentous inclusions of α-synuclein in the form of Lewy bodies and Lewy neurites in some brain cells, including dopaminergic nerve cells of the substantia nigra2. PD is increasingly recognised as a multisystem disorder, with cognitive decline being one of its most common non-motor symptoms. Many patients with PD develop dementia more than 10 years after diagnosis3. PD dementia (PDD) is clinically and neuropathologically similar to dementia with Lewy bodies (DLB), which is diagnosed when cognitive impairment precedes parkinsonian motor signs or begins within one year from their onset4. In PDD, cognitive impairment develops in the setting of well-established PD. Besides PD and DLB, multiple system atrophy (MSA) is the third major synucleinopathy5. It is characterized by the presence of abundant filamentous α-synuclein inclusions in brain cells, especially oligodendrocytes (Papp-Lantos bodies). We previously reported the electron cryo-microscopy structures of two types of α-synuclein filament extracted from the brains of individuals with MSA6. Each filament type is made of two different protofilaments. Here we report that the cryo-electron microscopy structures of α-synuclein filaments from the brains of individuals with PD, PDD and DLB are made of a single protofilament (Lewy fold) that is markedly different from the protofilaments of MSA. These findings establish the existence of distinct molecular conformers of assembled α-synuclein in neurodegenerative disease.


Assuntos
Química Encefálica , Encéfalo , Microscopia Crioeletrônica , Doença por Corpos de Lewy , alfa-Sinucleína , Humanos , alfa-Sinucleína/química , alfa-Sinucleína/metabolismo , alfa-Sinucleína/ultraestrutura , Encéfalo/metabolismo , Encéfalo/patologia , Encéfalo/ultraestrutura , Doença por Corpos de Lewy/patologia , Doença de Parkinson/complicações , Doença de Parkinson/patologia , Demência/complicações , Demência/patologia
20.
PLoS Biol ; 22(4): e3002559, 2024 Apr.
Artigo em Inglês | MEDLINE | ID: mdl-38652714

RESUMO

Increasing evidence indicates that terminally differentiated neurons in the brain may recommit to a cell cycle-like process during neuronal aging and under disease conditions. Because of the rare existence and random localization of these cells in the brain, their molecular profiles and disease-specific heterogeneities remain unclear. Through a bioinformatics approach that allows integrated analyses of multiple single-nucleus transcriptome datasets from human brain samples, these rare cell populations were identified and selected for further characterization. Our analyses indicated that these cell cycle-related events occur predominantly in excitatory neurons and that cellular senescence is likely their immediate terminal fate. Quantitatively, the number of cell cycle re-engaging and senescent neurons decreased during the normal brain aging process, but in the context of late-onset Alzheimer's disease (AD), these cells accumulate instead. Transcriptomic profiling of these cells suggested that disease-specific differences were predominantly tied to the early stage of the senescence process, revealing that these cells presented more proinflammatory, metabolically deregulated, and pathology-associated signatures in disease-affected brains. Similarly, these general features of cell cycle re-engaging neurons were also observed in a subpopulation of dopaminergic neurons identified in the Parkinson's disease (PD)-Lewy body dementia (LBD) model. An extended analysis conducted in a mouse model of brain aging further validated the ability of this bioinformatics approach to determine the robust relationship between the cell cycle and senescence processes in neurons in this cross-species setting.


Assuntos
Envelhecimento , Doença de Alzheimer , Encéfalo , Ciclo Celular , Senescência Celular , Neurônios , Animais , Humanos , Senescência Celular/genética , Encéfalo/metabolismo , Encéfalo/patologia , Envelhecimento/fisiologia , Envelhecimento/genética , Ciclo Celular/genética , Camundongos , Doença de Alzheimer/patologia , Doença de Alzheimer/genética , Doença de Alzheimer/metabolismo , Neurônios/metabolismo , Neurônios/patologia , Transcriptoma/genética , Doença de Parkinson/genética , Doença de Parkinson/patologia , Doença de Parkinson/metabolismo , Perfilação da Expressão Gênica , Masculino , Neurônios Dopaminérgicos/metabolismo , Neurônios Dopaminérgicos/patologia , Doenças Neurodegenerativas/genética , Doenças Neurodegenerativas/metabolismo , Doenças Neurodegenerativas/patologia , Camundongos Endogâmicos C57BL , Idoso
SELEÇÃO DE REFERÊNCIAS
DETALHE DA PESQUISA