Accumulation Of Alpha-synuclein Aggregates Research Articles

The Role of Astrocytes and Alpha-Synuclein in Parkinson’s Disease: A Review

The search for new therapies to reduce symptoms and find a cure for Parkinson’s disease has focused attention on two key points: the accumulation of alpha-synuclein aggregates and astrocytes. The former is a hallmark of the disease, while the latter corresponds to a type of glial cell with an important role in both the prevention and development of this neurodegenerative disorder. Traditionally, research has focused on therapies targeting dopaminergic neurons. Currently, as more is known about the genetic and molecular factors and the neuroglial interaction in the disease, great emphasis has been placed on the neuroprotective role of astrocytes in the early stages of the disease and on the astrocytic capture of alpha-synuclein under both physiological and pathological conditions. This review aims to analyze the contribution of alpha-synuclein and astrocytes to the development and progression of Parkinson’s disease, as well as to evaluate recent therapeutic proposals specifically focused on synucleopathies and astroglial cells as potential therapies for the disease.

Диагностика болезни Паркинсона. Часть 1. Возможности функциональной нейровизуализации

Objective of the Review: To describe available functional neuroimaging techniques for use in patients with Parkinson’s disease (PD). Key Points: Parkinson’s disease is a neurodegenerative disorder which affects 2-3% of people older than 65 years. The main neuropathological hallmarks of PD are an accumulation of alpha-synuclein aggregates in the cellular cytoplasm and a loss of neurons in the pars compacta of the substantia nigra, leading to dopamine deficiency. Clinical symptoms of the disease appear when the underlying neural impairment is already advanced, which significantly reduces treatment options. Over the two last decades, functional neuroimaging techniques such as positron emission tomography, single-photon emission computed tomography, proton magnetic resonance spectroscopy, and transcranial sonography have increasingly been used for diagnosing PD during patients’ lifetime and understanding the neuropathological mechanisms and compensatory reactions underlying its symptoms, as well as for monitoring the progression of PD. Conclusion: Modern functional neuroimaging techniques not only facilitate differential diagnosis of PD, but also make it possible to detect the disease at its early/preclinical stage. Keywords: Parkinson’s disease, neuroimaging, positron emission tomography, single-photon emission computed tomography, proton magnetic resonance spectroscopy, transcranial sonography.

Structure, function and toxicity of alpha-synuclein: the Bermuda triangle in synucleinopathies.

Parkinson's disease belongs to a group of currently incurable neurodegenerative disorders characterized by the misfolding and accumulation of alpha-synuclein aggregates that are commonly known as synucleinopathies. Clinically, synucleinopathies are heterogeneous, reflecting the somewhat selective neuronal vulnerability characteristic of each disease. The precise molecular underpinnings of synucleinopathies remain unclear, but the process of aggregation of alpha-synuclein appears as a central event. However, there is still no consensus with respect to the toxic forms of alpha-synuclein, hampering our ability to use the protein as a target for therapeutic intervention. To decipher the molecular bases of synucleinopathies, it is essential to understand the complex triangle formed between the structure, function and toxicity of alpha-synuclein. Recently, important steps have been undertaken to elucidate the role of the protein in both physiological and pathological conditions. Here, we provide an overview of recent findings in the field of alpha-synuclein research, and put forward a new perspective over paradigms that persist in the field. Establishing whether alpha-synuclein has a causative role in all synucleinopathies will enable the identification of targets for the development of novel therapeutic strategies for this devastating group of disorders. Alpha-synuclein is the speculated cornerstone of several neurodegenerative disorders known as Synucleinopathies. Nevertheless, the mechanisms underlying the pathogenic effects of this protein remain unknown. Here, we review the recent findings in the three corners of alpha-synuclein biology - structure, function and toxicity - and discuss the enigmatic roads that have accompanied alpha-synuclein from the beginning. This article is part of a special issue on Parkinson disease.

Region-Specific Alterations of Matrix Metalloproteinase Activity in Multiple System Atrophy.

MSA is a sporadic progressive neurodegenerative disorder characterized by a variable combination of parkinsonism, cerebellar ataxia, and autonomic dysfunction. The pathological hallmark of MSA is the accumulation of alpha-synuclein aggregates in the cytoplasm of oligodendrocytes along with neuronal loss and neuroinflammation, as well as blood-brain barrier dysfunction and myelin deterioration. Matrix metalloproteinases are zinc-dependent endopeptidases involved in the remodeling of the extracellular matrix, demyelination, and blood-brain barrier permeability. Several lines of evidence indicate a role for these enzymes in various pathological processes, including stroke, multiple sclerosis, Parkinson's, and Alzheimer's disease. This study aimed to assess potential alterations of matrix metalloproteinase-1, -2, -3, and -9 expression or activity in MSA postmortem brain tissue. Gelatin zymography revealed increased matrix metalloproteinase-2 activity in the putamen, but not in the frontal cortex, of MSA patients relative to controls. Immunohistochemistry revealed increased number of glial cells positive for matrix metalloproteinase-1, -2, and -3 in the putamen and frontal cortex of MSA patients. Double immunofluorescence revealed that matrix metalloproteinase-2 and -3 were expressed in astrocytes and microglia. Only matrix metalloproteinase-2 colocalized with alpha-synuclein in oligodendroglial cytoplasmic inclusions. These results demonstrate widespread alterations of matrix metalloproteinase expression in MSA and a pattern of increased matrix metalloproteinase-2 expression and activity affecting preferentially a brain region severely affected (putamen) over a relatively spared region (frontal cortex). Elevated matrix metalloproteinase expression may thus contribute to the disease process in MSA by promoting blood-brain barrier dysfunction and/or myelin degradation.

日本神経学会２００７年度楢林賞受賞者招待講演 パーキンソン病およびレビー小体型認知症の早期診断法の確立とその病態機序に関する研究

Cardiac uptake of meta-iodobenzylguanidine (MIBG) is specifically reduced in Lewy body disease (LBD). To see pathological basis of the reduced cardiac uptake of MIBG in LBD, we immunohistichemically examined cardiac tissues from patients with LBD, related movement disorders and Alzheimer's disease (AD). In LBD, cardiac sympathetic denervation occurs, which accounts for the reduced cardiac uptake of MIBG. Patients with LBD have Lewy bodies (LBs) in the nervous system, whereas patients with the other neurodegenerative parkinsonism, parkin-associated Parkinson's disease (PD) and AD and have no LBs. Therefore, cardiac sympathetic denervation is closely related to the presence of LBs in a wide range of neurodegenerative processes. We further investigate how a-synuclein aggregates are involved in degeneration of the cardiac sympathetic nerve in PD. Accumulation of alpha-synuclein aggregates in the distal axons of the cardiac sympathetic nervous system precedes that of neuronal somata or neurites in the paravertebral sympathetic ganglia and that it heralds centripetal degeneration of the cardiac sympathetic nerve in PD. This chronological and dynamic relationship between alpha-synuclein aggregates and degeneration of the cardiac sympathetic nervous system may represent the pathological mechanism underlying a common degenerative process in PD.