The third exon of the  synuclein gene from a normal person and two Vietnamese persons with Prkinson’s disease was subcloned and sequenced. It was shown that in all cases there are two additional bases in the positions of C461 and T511. That is quite different from the sequence with DDBJ/Genbank accession number U46898. Besides, a mutation T543G was revealed in one Parkinson’s disease patien. All mentioned changes were located outside the region coding for third exon (G401-G442).
alpha-Synuclein ; Parkinson Disease

No abstract available.
alpha-Synuclein ; Colon ; Parkinson Disease

Parkinson's Disease (PD) is a complex and multifactorial disorder of both idiopathic and genetic origin. Thus far, more than 20 genes have been linked to familial forms of PD. Two of these genes encode for ATP13A2 and alpha-synuclein (asyn), proteins that seem to be members of a common network in both physiological and disease conditions. Thus, two different hypotheses have emerged supporting a role of ATP13A2 and asyn in metal homeostasis or in autophagy. Interestingly, an appealing theory might combine these two cellular pathways. Here we review the novel findings in the interaction between these two proteins and debate the exciting roads still ahead.
alpha-Synuclein* ; Autophagy* ; Homeostasis ; Parkinson Disease

Humans ; alpha-Synuclein/genetics* ; Parkinson Disease/pathology*

Parkinson's disease is a multifactorial disorder with several genes linked to the familial types of the disease. ATP13A2 is one of those genes and encode for a transmembrane protein localized in lysosomes and late endosomes. Previous studies suggested the roles of this protein in lysosomal functions and cellular ion homeostasis. Here, we set out to investigate the role of ATP13A2 in lysosomal function and in metabolism of alpha-synuclein, another PD-linked protein whose accumulation is implicated in the pathogenesis. We generated non-sense mutations in both copies of ATP13A2 gene in SH-SY5Y human neuroblastoma cells. We examined lysosomal function of ATP13A2-/- cells by measuring the accumulation of lysosomal substrate proteins, such as p62 and polyubiquitinated proteins, induction of acidic compartments, and degradation of ectopically introduced dextran. None of these measures were altered by ATP13A2 deficiency. The steady-state levels of alpha-synuclein in cells or secretion of this protein were unaltered either in ATP13A2-/- compared to the normal cells. Therefore, the proposed roles of ATP13A2 in lysosomal functions may not be generalized and may depend on the cellular context. The ATP13A2-/- cells generated in the current study may provide a useful control for studies on the roles of PD genes in lysosomal functions.
alpha-Synuclein* ; Dextrans ; Endosomes ; Homeostasis ; Humans ; Lysosomes ; Metabolism* ; Neuroblastoma ; Parkinson Disease ; Polyubiquitin

Converging lines of evidence suggest that cell-to-cell transmission and the self-propagation of pathogenic amyloidogenic proteins play a central role in the initiation and the progression of several neurodegenerative disorders. This "prion-like" hypothesis has been recently reported for alpha-synuclein, a presynaptic protein implicated in the pathogenesis of Parkinson's disease (PD) and related disorders. This review summarizes recent findings on alpha-synuclein prion-like propagation, focusing on its transmission, seeding and degradation and discusses some key questions that remain to be explored. Understanding how alpha-synuclein exits cells and propagates from one brain region to another will lead to the development of new therapeutic strategies for the treatment of PD, aiming at slowing or stopping the disease progression.
alpha-Synuclein* ; Amyloidogenic Proteins ; Brain ; Disease Progression ; Neurodegenerative Diseases ; Parkinson Disease

Alpha-synuclein is a small neuronal protein that is closely associated with the etiology of Parkinson's disease. Mutations in and alterations in expression levels of alpha-synuclein cause autosomal dominant early onset heredity forms of Parkinson's disease, and sporadic Parkinson's disease is defined in part by the presence of Lewy bodies and Lewy neurites that are composed primarily of alpha-synuclein deposited in an aggregated amyloid fibril state. The normal function of alpha-synuclein is poorly understood, and the precise mechanisms by which it leads to toxicity and cell death are also unclear. Although alpha-synuclein is a highly soluble, cytoplasmic protein, it binds to a variety of cellular membranes of different properties and compositions. These interactions are considered critical for at least some normal functions of alpha-synuclein, and may well play critical roles in both the aggregation of the protein and its mechanisms of toxicity. Here we review the known features of alpha-synuclein membrane interactions in the context of both the putative functions of the protein and of its pathological roles in disease.
alpha-Synuclein* ; Amyloid ; Cell Death ; Cytoplasm ; Heredity ; Lewy Bodies ; Membranes* ; Neurites ; Neurons ; Parkinson Disease ; Synaptic Transmission

Multiple system atrophy (MSA) is a rare, late-onset and fatal neurodegenerative disease including multisystem neurodegeneration and the formation of alpha-synuclein containing oligodendroglial cytoplasmic inclusions (GCIs), which present the hallmark of the disease. MSA is considered to be a sporadic disease; however certain genetic aspects have been studied during the last years in order to shed light on the largely unknown etiology and pathogenesis of the disease. Epidemiological studies focused on the possible impact of environmental factors on MSA disease development. This article gives an overview on the findings from genetic and epigenetic studies on MSA and discusses the role of genetic or epigenetic factors in disease pathogenesis.
alpha-Synuclein ; Epigenomics* ; Genetics ; Inclusion Bodies ; Multiple System Atrophy* ; Neurodegenerative Diseases

Parkinson's disease (PD) is a common neurodegenerative disorder associated with aging. Great progresses have been made toward understanding the pathogenesis over the past decades. It seems that both genetic factors and environmental factors contribute to PD, while the precise pathogenesis still remains unknown. Recently, increasing evidence has suggested that autophagy dysregulation is closely related to PD. Dysregulation of the autophagic pathways has been observed in the brains of PD patients or in animal models of PD, and a number of PD-associated proteins, such as a-synuclein, Parkin and PINK1, were found to involve in autophagy, suggesting a link between autophagy and pathogenesis of PD. In this review, we summarized the role of PD-associated proteins in autophagy pathways. In addition, we described the efficacy of autophagy-modulating compounds in PD models and discussed promising strategies for PD therapy.
Animals ; Autophagy ; Humans ; Parkinson Disease ; physiopathology ; Protein Kinases ; metabolism ; Ubiquitin-Protein Ligases ; metabolism ; alpha-Synuclein ; metabolism

Parkinson's disease (PD), a progressive neurodegenerative disorder, is pathologically characterized by the progressive loss of dopaminergic neurons in the substantia nigra pars compacta (SNpc) and the presence of deposits of aggregated α-synuclein in intracellular inclusions known as Lewy bodies (LB). A highly localized inflammatory response mediated by reactive microglia is prominent in PD brains, but the mechanisms underlying the microglial activation are poorly understood. Recently some lines of evidences have shown that monomeric, or aggregated α-synuclein can activate microglia, the toxic factors released from activated microglia may lead to the cell death of dopaminergic neurons. This review is to summarize the recent progress on the role of α-synuclein induced microglia activation on the PD pathogenesis and progression, and to discuss the possible mechanisms involved.
Humans ; Microglia ; pathology ; Parkinson Disease ; etiology ; metabolism ; pathology ; alpha-Synuclein ; chemistry ; metabolism ; physiology