Retinal α-synuclein deposits in Parkinson’s disease patients and animal models

Despite decades of research, accurate diagnosis of Parkinson’s disease remains a challenge, and disease-modifying treatments are still lacking. Research into the early (presymptomatic) stages of Parkinson’s disease and the discovery of novel biomarkers is of utmost importance to reduce this burden and to come to a more accurate diagnosis at the very onset of the disease. Many have speculated that non-motor symptoms could provide a breakthrough in the quest for early biomarkers of Parkinson’s disease, including the visual disturbances and retinal abnormalities that are seen in the majority of Parkinson’s disease patients. An expanding number of clinical studies have investigated the use of in vivo assessments of retinal structure, electrophysiological function, and vision-driven tasks as novel means for identifying patients at risk that need further neurological examination and for longitudinal follow-up of disease progression in Parkinson’s disease patients. Often, the results of these studies have been interpreted in relation to α-synuclein deposits and dopamine deficiency in the retina, mirroring the defining pathological features of Parkinson’s disease in the brain. To better understand the visual defects seen in Parkinson’s disease patients and to propel the use of retinal changes as biomarkers for Parkinson’s disease, however, more conclusive neuropathological evidence for the presence of retinal α-synuclein aggregates, and its relation to the cerebral α-synuclein burden, is urgently needed. This review provides a comprehensive and critical overview of the research conducted to unveil α-synuclein aggregates in the retina of Parkinson’s disease patients and animal models, and thereby aims to aid the ongoing discussion about the potential use of the retinal changes and/or visual symptoms as biomarkers for Parkinson’s disease.LV and LDG are supported by the Research Foundation Flanders (fellowships 1S51718N and 12I3817N). IOL acknowledges financial support from the Ministerio de Educación, Spain (FPU 14/03166). NC acknowledges financial support from the Ministerio de Economía y Competitividad, Spain (MINECO-FEDER-BFU2015-67139-R), Generalitat Valenciana (Prometeo 2016/158), and Instituto Carlos III (ISCIII RETICS-FEDER RD16/0008/0016). The Brain and Body Donation Program has been supported by the National Institute of Neurological Disorders and Stroke (U24 NS072026), the National Institute on Aging (P30 AG19610), the Arizona Department of Health Services, the Arizona Biomedical Research Commission, and the Michael J. Fox Foundation for Parkinson’s Research

MMP-3 deficiency alleviates endotoxin-induced acute inflammation in the posterior eye segment

Matrix metalloproteinase-3 (MMP-3) is known to mediate neuroinflammatory processes by activating microglia, disrupting blood-central nervous system barriers and supporting neutrophil influx into the brain. In addition, the posterior part of the eye, more specifically the retina, the retinal pigment epithelium (RPE) and the blood-retinal barrier, is affected upon neuroinflammation, but a role for MMP-3 during ocular inflammation remains elusive. We investigated whether MMP-3 contributes to acute inflammation in the eye using the endotoxin-induced uveitis (EIU) model. Systemic administration of lipopolysaccharide induced an increase in MMP-3 mRNA and protein expression level in the posterior part of the eye. MMP-3 deficiency or knockdown suppressed retinal leukocyte adhesion and leukocyte infiltration into the vitreous cavity in mice subjected to EIU. Moreover, retinal and RPE mRNA levels of intercellular adhesion molecule 1 (Icam1), interleukin 6 (Il6), cytokine-inducible nitrogen oxide synthase (Nos2) and tumor necrosis factor alpha (Tnf alpha), which are key molecules involved in EIU, were clearly reduced in MMP-3 deficient mice. In addition, loss of MMP-3 repressed the upregulation of the chemokines monocyte chemoattractant protein (MCP)-1 and (C-X-C motif) ligand 1 (CXCL1). These findings suggest a contribution of MMP-3 during EIU, and its potential use as a therapeutic drug target in reducing ocular inflammation

Platelet-Associated Matrix Metalloproteinases Regulate Thrombus Formation and Exert Local Collagenolytic Activity

Objective Platelets are increasingly implicated in processes beyond hemostasis and thrombosis, such as vascular remodeling. Members of the matrix metalloproteinase (MMP) family not only remodel the extracellular matrix but also modulate platelet function. Here, we made a systematic comparison of the roles of MMP family members in acute thrombus formation under flow conditions and assessed platelet-dependent collagenolytic activity over time. Approach and Results Pharmacological inhibition of MMP-1 or MMP-2 (human) or deficiency in MMP-2 (mouse) suppressed collagen-dependent platelet activation and thrombus formation under flow, whereas MMP-9 inhibition/deficiency stimulated these processes. The absence of MMP-3 was without effect. Interestingly, MMP-14 inhibition led to the formation of larger thrombi, which occurred independently of its capacity to activate MMP-2. Platelet thrombi exerted local collagenolytic activity capable of cleaving immobilized dye-quenched collagen and fibrillar collagen fibers within hours, with loss of the majority of the platelet adhesive properties of collagen as a consequence. This collagenolytic activity was redundantly mediated by platelet-associated MMP-1, MMP-2, MMP-9, and MMP-14 but occurred independently of platelet -granule release (Nbeal2(-/-) mice). The latter was in line with subcellular localization experiments, which indicated a granular distribution of MMP-1 and MMP-2 in platelets, distinct from -granules. Whereas MMP-9 protein could not be detected inside platelets, activated platelets did bind plasma-derived MMP-9 to their plasma membrane. Overall, platelet MMP activity was predominantly membrane-associated and influenced by platelet activation status. Conclusions Platelet-associated MMP-1, MMP-2, MMP-9, and MMP-14 differentially modulate acute thrombus formation and at later time points limit thrombus formation by exerting collagenolytic activity

Matrix metalloproteinases in glaucoma: targets for novel therapeutic approaches?

Matrix metalloproteinases (MMPs), a family of Zn2+-dependent proteases, were originally named after their ability to cleave and remodel the extracellular matrix (ECM), however, their substrate repertoire has proven to be much broader, comprising other proteinases, growth factors, signaling molecules, cell surface receptors, and even intracellular targets. By proteolytic cleavage, MMPs modify the structure and activity of these substrates, and add a complex extra dimension of biological control. As a result, MMPs are important regulatory nodes in the protease web, a complex network of interactions that regulates protease activities and determines the functional state of the proteome and cell activity. Deregulated MMP activity is a common characteristic of many diseases, including neurodegenerative disorders such as glaucoma, multiple sclerosis, Huntington’s disease, Alzheimer’s disease, Parkinson’s disease, etc. Nevertheless, despite their detrimental impact during central nervous system (CNS) pathology, there is ample evidence corroborating MMPs as fine regulators of CNS physiology, and well-balanced MMP activity is instrumental to CNS development, plasticity and repair. Multiple studies in glaucoma patients and in animal models of spontaneous and experimentally induced glaucoma, reported changes in the expression and activity of several MMPs in the retina, optic nerve, aqueous humor and trabecular meshwork. These data have led to the hypothesis that MMPs might be involved in glaucoma onset and/or disease progression. However, reports are conflicting and research aiming at providing a clear definition of their causative role is lacking. With this work, we intend to contribute to a better understanding of the role of MMPs during glaucoma pathogenesis and to the development of much-needed novel therapeutic approaches to treat this optic neuropathy. Indeed, with more than 65 million patients worldwide, and still on the increase, glaucoma is and will be a major concern for ophthalmologists today and in the future. Current baroprotective therapies allow to reduce intraocular pressure in the majority of glaucoma patients and to halt -yet not reverse- disease progression. Nevertheless, a sizeable percentage of patients do not benefit from this therapeutic approach, and, as no alternatives are available, experience progressive vision loss. Four MMPs, namely MMP-2, MMP-3, MMP-9 and MT1-MMP, are the subject of different experimental approaches, aiming to answer the central question: “Can we identify MMPs as novel targets for the development of baroprotective, neuroprotective and/or regenerative therapeutic strategies for the treatment of glaucoma?”status: publishe

Molecular Mechanisms of Neural Circuit Development and Regeneration

The human brain contains 86 billion neurons [...

Is the eye an extension of the brain in CNS disease?

status: publishe