RESUMEN
Parkinson's disease (PD) is the second most common neurodegenerative disorder and the fastest growing neurologic disease in the world, yet no disease-modifying therapy is available for this disabling condition. Multiple lines of evidence implicate the protein α-synuclein (α-Syn) in the pathogenesis of PD, and as such, there is intense interest in targeting α-Syn for potential disease modification. α-Syn is also a key pathogenic protein in other synucleionpathies, most commonly dementia with Lewy bodies. Thus, therapeutics targeting this protein will have utility in these disorders as well. Here we discuss the various approaches that are being investigated to prevent and mitigate α-Syn toxicity in PD, including clearing its pathologic aggregates from the brain using immunization strategies, inhibiting its misfolding and aggregation, reducing its expression level, enhancing cellular clearance mechanisms, preventing its cell-to-cell transmission within the brain and perhaps from the periphery, and targeting other proteins associated with or implicated in PD that contribute to α-Syn toxicity. We also discuss the therapeutics in the pipeline that harness these strategies. Finally, we discuss the challenges and opportunities for the field in the discovery and development of therapeutics for disease modification in PD. SIGNIFICANCE STATEMENT: PD is the second most common neurodegenerative disorder, for which disease-modifying therapies remain a major unmet need. A large body of evidence points to α-synuclein as a key pathogenic protein in this disease as well as in dementia with Lewy bodies, making it of leading therapeutic interest. This review discusses the various approaches being investigated and progress made to date toward discovering and developing therapeutics that would slow and stop progression of these disabling diseases.
Asunto(s)
Enfermedades Neurodegenerativas , Enfermedad de Parkinson , Encéfalo/metabolismo , Humanos , Cuerpos de Lewy/metabolismo , Enfermedad de Parkinson/tratamiento farmacológico , alfa-Sinucleína/metabolismoRESUMEN
PURPOSE OF THE REVIEW: Inflammation is a key component in the pathogenesis of cerebrovascular diseases. In the past few years, the role of systemic infection and gut dysbiosis in modulating inflammation and stroke risk has been increasingly acknowledged. In this review, we synthesize contemporary literature on the effects of infection and inflammation on stroke risk and outcomes, with a focus on periodontal disease, COVID-19 infection, and gut dysbiosis. RECENT FINDINGS: Chronic and acute infections such as periodontitis and COVID-19 induce systemic inflammation that cause atherogenesis and increase cardiac injury and arrhythmias. These infections also directly injure the endothelium leading to worsened secondary inflammation after stroke. Gut dysbiosis engenders a pro-inflammatory state by modulating intestinal lymphocyte populations that can traffic directly to the brain. Additionally, post-stroke immune dysregulation creates a compounding feedback loop of further infections and gut dysbiosis that worsen outcomes. Recent advances in understanding the pathophysiology of how infection and dysbiosis affect the progression of stroke, as well as long-term recovery, have revealed tantalizing glimpses at potential therapeutic targets. We discuss the multidirectional relationship between stroke, infection, and gut dysbiosis, and identify areas for future research to further explore therapeutic opportunities.
Asunto(s)
COVID-19 , Microbioma Gastrointestinal , Accidente Cerebrovascular , COVID-19/complicaciones , Disbiosis/complicaciones , Humanos , Inflamación/complicaciones , Accidente Cerebrovascular/complicaciones , Accidente Cerebrovascular/etiologíaRESUMEN
The ability of DJ-1 to modulate signal transduction has significant effects on how the cell regulates normal processes such as growth, senescence, apoptosis, and autophagy to adapt to changing environmental stimuli and stresses. Perturbations of DJ-1 levels or function can disrupt the equilibrium of homeostatic signaling networks and set off cascades that play a role in the pathogenesis of conditions such as cancer and Parkinson's disease.DJ-1 plays a major role in various pathways. It mediates cell survival and proliferation by activating the extracellular signal-regulated kinase (ERK1/2) pathway and the phosphatidylinositol-3-kinase (PI3K)/Akt pathway. It attenuates cell death signaling by inhibiting apoptosis signal-regulating kinase 1 (ASK1) activation as well as by inhibiting mitogen-activated protein kinase kinase kinase 1 (MEKK1/MAP3K1) activation of downstream apoptotic cascades. It also modulates autophagy through the ERK, Akt, or the JNK/Beclin1 pathways. In addition, DJ-1 regulates the transcription of genes essential for male reproductive function, such as spermatogenesis, by relaying nuclear receptor androgen receptor (AR) signaling. In this chapter, we summarize the ways that DJ-1 regulates these pathways, focusing on how its role in signal transduction contributes to cellular homeostasis and the pathologic states that result from dysregulation.
Asunto(s)
Neoplasias/metabolismo , Enfermedad de Parkinson/metabolismo , Proteína Desglicasa DJ-1/metabolismo , Mapas de Interacción de Proteínas , Transducción de Señal , Animales , Humanos , Modelos BiológicosRESUMEN
BACKGROUND AND OBJECTIVES: Factors associated with external ventricular catheter tract hemorrhage (CTH) are well studied; whether CTH adversely influence outcomes after intracerebral hemorrhage (sICH), however, is poorly understood. We therefore sought to evaluate the association between CTH and sICH outcomes. METHODS: We performed a post hoc analysis of the Clot Lysis: Evaluating Accelerated Resolution of Intraventricular Hemorrhage trial. The exposure was CTH and evaluated on serial computed tomography scans between admission and randomization (approximately 72 hours). The primary outcomes were a composite of death or major disability (modified Rankin Score >3) and mortality alone, both assessed at 6 months. Secondary outcomes were functional outcomes at 30 days, permanent cerebrospinal fluid (CSF) shunt placement, any infection, and ventriculitis. We performed logistic regression adjusted for demographics, comorbidities, sICH characteristics, and treatment assignment, for all analyses. RESULTS: Of the 500 patients included, the mean age was 59 (SD, ±11) years and 222 (44%) were female. CTH occurred in 112 (22.4%) patients and was more common in minority patients, those on prior antiplatelet therapy, and patients who had more than 1 external ventricular drain placed. The end of treatment intraventricular hemorrhage volume was higher among patients with CTH (11.7 vs 7.9 mL, P = .01), but there were no differences in other sICH characteristics or the total duration of external ventricular drain. In multivariable regression models, CTH was not associated with death or major disability (odds ratio, 0.7; 95% CI: 0.4-1.2) or death alone (odds ratio, 0.8; 95% CI, 0.5-1.4). There were no relationships between CTH and secondary outcomes including 30-day functional outcomes, permanent CSF shunt placement, any infection, or ventriculitis. CONCLUSION: Among patients with sICH and large intraventricular hemorrhage, CTH was not associated with poor sICH outcomes, permanent CSF shunt placement, or infections. A more detailed cognitive evaluation is needed to inform about the role of CTH in sICH prognosis.
Asunto(s)
Ventriculitis Cerebral , Humanos , Femenino , Persona de Mediana Edad , Masculino , Hemorragia Cerebral/cirugía , Derivaciones del Líquido Cefalorraquídeo , Pronóstico , Catéteres , Resultado del TratamientoRESUMEN
DJ-1 is a highly conserved multifunctional protein linked to both neurodegeneration and neoplasia. Among its various activities is an antioxidant property leading to cytoprotection under oxidative stress conditions. This is associated with the ability to modulate signal transduction events that determine how the cell regulates normal processes such as growth, senescence, apoptosis, and autophagy in order to adapt to environmental stimuli and stresses. Alterations in DJ-1 expression or function can disrupt homeostatic signaling networks and initiate cascades that play a role in the pathogenesis of conditions such as Parkinson's disease and cancer. DJ-1 plays a major role in various signaling pathways. Related to its anti-oxidant properties, it mediates cell survival and proliferation by activating the extracellular signal-regulated kinase (ERK1/2) pathway and attenuates cell death signaling by inhibiting apoptosis signal-regulating kinase 1 (ASK1) activation. Here, we review the ways through which DJ-1 regulates these pathways, focusing on how its regulation of signal transduction contributes to cellular homeostasis and the pathologic states that result from their dysregulation.
Asunto(s)
MAP Quinasa Quinasa Quinasa 5/metabolismo , Sistema de Señalización de MAP Quinasas , Estrés Oxidativo , Proteína Desglicasa DJ-1/metabolismo , Transducción de Señal , Animales , Muerte Celular , Proliferación Celular , Supervivencia Celular , Citoprotección , HumanosRESUMEN
DJ-1 is a highly conserved protein that protects neurons against oxidative stress and whose loss of function mutations are linked to recessively inherited Parkinson's disease (PD). While a number of signaling pathways have been shown to be regulated by DJ-1, its role in controlling cell survival through non-coding RNAs remains poorly understood. Here, using a microarray screen, we found that knocking down DJ-1 in human neuroblastoma cells results in down-regulation of microRNA-221 (miR-221). This is one of the most abundant miRNAs in the human brain and promotes neurite outgrowth and neuronal differentiation. Yet the molecular mechanism linking miR-221 to genetic forms of PD has not been studied. Consistent with the microarray data, miR-221 expression is also decreased in DJ-1-/- mouse brains. Re-introduction of wild-type DJ-1, but not its PD-linked pathogenic M26I mutant, restores miR-221 expression. Notably, over-expression of miR-221 is protective against 1-methyl-4-phenylpyridinium (MPP+)-induced cell death, while inhibition of endogenous miR-221 sensitizes cells to this toxin. Additionally, miR-221 down-regulates the expression of several pro-apoptotic proteins at basal conditions and prevents oxidative stress-induced up-regulation of bcl-2-like protein 11 (BIM). Accordingly, miR-221 protects differentiated DJ-1 knock-down ReNcell VM human dopaminergic neuronal cells from MPP+-induced neurite retraction and cell death. DJ-1 is a known activator of the mitogen-activated protein kinase (MAPK)/extracellular-regulated kinase (ERK) pathway and may modulate miR-221 levels in part through this pathway. We found that inhibiting ERK1/2 decreases miR-221 levels, whereas over-expressing ERK1 in DJ-1 knock-down cells increases miR-221 levels. These findings point to a new cytoprotective mechanism by which DJ-1 may increase miR-221 expression through the MAPK/ERK pathway, subsequently leading to repression of apoptotic molecules. The inability of a pathogenic DJ-1 mutant to modulate miR-221 further supports the relevance of this mechanism in neuronal health and its failure in DJ-1-linked PD.