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Cellular and Molecular Life Sciences :... Sep 2007alpha-Synuclein belongs to a small group of natively unfolded proteins that can transiently bind to lipid membranes and acquire a partial alpha-helical conformation.... (Review)
Review
alpha-Synuclein belongs to a small group of natively unfolded proteins that can transiently bind to lipid membranes and acquire a partial alpha-helical conformation. Under certain pathogenic conditions, alpha-synuclein aggregates to form oligomers and insoluble fibrils with increased ss-sheet configuration. Although genetic mutations and multiplications of the gene have been found in familial cases, the mechanism by which this protein aggregates in sporadic cases of Parkinson's disease, dementia with Lewy bodies and multisystem atrophy is not fully understood. Here we review the function of alpha-synuclein and recent insight into the mechanisms by which it aggregates.
Topics: Humans; Lewy Bodies; Parkinson Disease; Protein Processing, Post-Translational; Protein Structure, Tertiary; alpha-Synuclein
PubMed: 17605001
DOI: 10.1007/s00018-007-7217-5 -
Journal of Parkinson's Disease 2019
Topics: Adolescent; Adult; Aged; Aged, 80 and over; Clinical Trial Protocols as Topic; Clinical Trials as Topic; Humans; Immunotherapy; Middle Aged; Parkinson Disease; Young Adult; alpha-Synuclein
PubMed: 30741694
DOI: 10.3233/JPD-189004 -
The therapeutical potential of alpha-synuclein antiaggregatory agents for dementia with Lewy bodies.Current Medicinal Chemistry 2008Dementia with Lewy bodies (DLB), the second most frequent cause of dementia after Alzheimer disease (AD), is characterized by the widespread distribution of Lewy bodies... (Review)
Review
Dementia with Lewy bodies (DLB), the second most frequent cause of dementia after Alzheimer disease (AD), is characterized by the widespread distribution of Lewy bodies in virtually every brain area. Clinically, DLB is distinguished from AD by fluctuating cognition, prominent visual hallucinations and parkinsonism, and from Parkinson disease, by the appearance of parkinsonism within one year of cognitive or behavioral decline. The main component of Lewy bodies is alpha-synuclein. Accumulating evidence suggests that its aggregation constitutes one of the first steps preceding Lewy body formation, so that antiaggregation strategies would be very useful to prevent alpha-synuclein fibril formation. Main therapies nevertheless applied up to the present remain symptomatological. In this context, cholinesterase inhibitors such as rivastigmine, galantamine and donepezil, are used for the treatment of delusions and other psychotic symptoms. This review focuses on the recent discovery of possible alpha-synuclein anti-aggregation factors, where four main classes can be defined. First, beta-synuclein as well as alpha-synuclein derived peptides in addition to antibodies present a group of proteins and peptides that directly interact with alpha-synuclein and so inhibit its aggregation. Second, small molecules interfere with alpha-synuclein aggregation by their covalent binding, although not all of them are suitable for an appropriate inhibition of alpha-synuclein aggregation. Third, to inhibit the expression of alpha-synuclein and its isoforms at the RNA level, the use of interference RNA represents a future challenge. The fourth strategy is based on the enhancement of inclusion body formation to accelerate the elimination of soluble alpha-synuclein oligomers. Each chapter section includes the discussion of possible strategies for the development of drugs and therapies.
Topics: Amino Acid Sequence; Humans; Lewy Body Disease; Molecular Sequence Data; Protein Binding; alpha-Synuclein
PubMed: 18991634
DOI: 10.2174/092986708786242868 -
Cells Nov 2021Alpha-synucleinopathies comprise progressive neurodegenerative diseases, including Parkinson's disease (PD), dementia with Lewy bodies (DLB), and multiple system atrophy... (Review)
Review
Alpha-synucleinopathies comprise progressive neurodegenerative diseases, including Parkinson's disease (PD), dementia with Lewy bodies (DLB), and multiple system atrophy (MSA). They all exhibit the same pathological hallmark, which is the formation of α-synuclein positive deposits in neuronal or glial cells. The aggregation of α-synuclein in the cell body of neurons, giving rise to the so-called Lewy bodies (LBs), is the major characteristic for PD and DLB, whereas the accumulation of α-synuclein in oligodendroglial cells, so-called glial cytoplasmic inclusions (GCIs), is the hallmark for MSA. The mechanisms involved in the intracytoplasmic inclusion formation in neuronal and oligodendroglial cells are not fully understood to date. A possible mechanism could be an impaired autophagic machinery that cannot cope with the high intracellular amount of α-synuclein. In fact, different studies showed that reduced autophagy is involved in α-synuclein aggregation. Furthermore, altered levels of different autophagy markers were reported in PD, DLB, and MSA brains. To date, the trigger point in disease initiation is not entirely clear; that is, whether autophagy dysfunction alone suffices to increase α-synuclein or whether α-synuclein is the pathogenic driver. In the current review, we discuss the involvement of defective autophagy machinery in the formation of α-synuclein aggregates, propagation of α-synuclein, and the resulting neurodegenerative processes in α-synucleinopathies.
Topics: Animals; Autophagy; Disease Models, Animal; Humans; Neurons; Oligodendroglia; Synucleinopathies; alpha-Synuclein
PubMed: 34831366
DOI: 10.3390/cells10113143 -
Biomolecules May 2015Mutations and duplication/triplication of the alpha-synuclein (αSyn)-coding gene have been found to cause familial Parkinson's disease (PD), while genetic polymorphisms... (Review)
Review
Mutations and duplication/triplication of the alpha-synuclein (αSyn)-coding gene have been found to cause familial Parkinson's disease (PD), while genetic polymorphisms in the region controlling the expression level and stability of αSyn have been identified as risk factors for idiopathic PD, pointing to the importance of wild-type (wt) αSyn dosage in the disease. Evidence that αSyn is present in the cerebrospinal fluid and interstitial brain tissue and that healthy neuronal grafts transplanted into PD patients often degenerate suggests that extracellularly-released αSyn plays a role in triggering the neurodegenerative process. αSyn's role in neurotransmission has been shown in various cell culture models in which the protein was upregulated or deleted and in knock out and transgenic animal, with different results on αSyn's effect on synaptic vesicle pool size and mobilization, αSyn being proposed as a negative or positive regulator of neurotransmitter release. In this review, we discuss the effect of αSyn on pre- and post-synaptic compartments in terms of synaptic vesicle trafficking, calcium entry and channel activity, and we focus on the process of exocytosis and internalization of αSyn and on the spreading of αSyn-driven effects due to the presence of the protein in the extracellular milieu.
Topics: Animals; Exocytosis; Humans; Parkinson Disease; Synaptic Transmission; alpha-Synuclein
PubMed: 25985082
DOI: 10.3390/biom5020865 -
Biochimie Sep 2015Dimer formation is likely the first step in the oligomerization of α-synuclein in Lewy bodies. In order to prevent α-synuclein aggregation, knowledge of the atomistic...
Dimer formation is likely the first step in the oligomerization of α-synuclein in Lewy bodies. In order to prevent α-synuclein aggregation, knowledge of the atomistic structures of possible α-synuclein dimers and the interaction affinity between the dimer domains is a necessary prerequisite in the process of rational design of dimerization inhibitors. Using computational methodology, we have investigated several possible α-synuclein dimer structures, focusing on dimers formed from α-helical forms of the protein found when it is membrane-bound, and dimers formed from β-sheet conformations predicted by simulations. Structures and corresponding binding affinities for the interacting monomers in possible α-synuclein dimers, along with properties including the contributions from different interaction energies and the radii of gyration, were found through molecular docking followed by MD simulations and binding-energy calculations. We found that even though α-synuclein is highly charged, hydrophobic contributions play a significant role in stabilizing dimers.
Topics: Dimerization; Hydrophobic and Hydrophilic Interactions; Molecular Dynamics Simulation; Protein Structure, Secondary; Protein Structure, Tertiary; alpha-Synuclein
PubMed: 26193124
DOI: 10.1016/j.biochi.2015.07.011 -
Molecular Neurobiology Apr 2013Parkinson's disease (PD) is the second most common neurodegenerative disorder, defined by the presence of resting tremor, muscular rigidity, bradykinesia, and postural... (Review)
Review
Parkinson's disease (PD) is the second most common neurodegenerative disorder, defined by the presence of resting tremor, muscular rigidity, bradykinesia, and postural instability. PD is characterized by the progressive loss of dopaminergic neurons within the substantia nigra pars compacta of the midbrain. The neuropathological hallmark of the disease is the presence of intracytoplasmic inclusions, called Lewy bodies (LBs) and Lewy neurites (LNs), containing α-synuclein, a small protein which is widely expressed in the brain. The α-synuclein gene, SNCA, is located on chromosome 4q22.1; SNCA-linked PD shows an autosomal dominant inheritance pattern with a relatively early onset age, and it usually progresses rapidly. Three missense mutations, A53T, A30P, and E46K, in addition to gene multiplications of the SNCA have been described so far. Although it is clear that LBs and LNs contain mainly the α-synuclein protein, the mechanism(s) which leads α-synuclein to accumulate needs to be elucidated. The primary question in the molecular pathology of PD is how wild-type α-synuclein aggregates in PD, and which interacting partner(s) plays role(s) in the aggregation process. It is known that dopamine synthesis is a stressfull event, and α-synuclein expression somehow affects the dopamine synthesis. The aberrant interactions of α-synuclein with the proteins in the dopamine synthesis pathway may cause disturbances in cellular mechanisms. The normal physiological folding state of α-synuclein is also important for the understanding of pathological aggregates. Recent studies on the α-synuclein protein and genome-wide association studies of the α-synuclein gene show that PD has a strong genetic component, and both familial and idiopathic PD have a common denominator, α-synuclein, at the molecular level. It is clear that the disease process in Parkinson's disease, as in other neurodegenerative disorders, is very complicated; there can be several different molecular pathways which are responsible for diverse and possibly also unrelated functions inside the neuron, playing roles in PD pathogenesis.
Topics: Animals; Brain Chemistry; Humans; Parkinson Disease; alpha-Synuclein
PubMed: 23180276
DOI: 10.1007/s12035-012-8369-3 -
Journal of Parkinson's Disease 2021The use of wildtype recombinant alpha-synuclein preformed fibrils (aSyn PFFs) to induce endogenous alpha-synuclein to form pathological phosphorylation and trigger... (Review)
Review
The use of wildtype recombinant alpha-synuclein preformed fibrils (aSyn PFFs) to induce endogenous alpha-synuclein to form pathological phosphorylation and trigger neurodegeneration is a popular model for studying Parkinson's disease (PD) biology and testing therapeutic strategies. The strengths of this model lie in its ability to recapitulate the phosphorylation/aggregation of aSyn and nigrostriatal degeneration seen in PD, as well as its suitability for studying the progressive nature of PD and the spread of aSyn pathology. Although the model is commonly used and has been adopted by many labs, variability in observed phenotypes exists. Here we provide summaries of the study design and reported phenotypes from published reports characterizing the aSyn PFF in vivo model in rodents following injection into the brain, gut, muscle, vein, peritoneum, and eye. These summaries are designed to facilitate an introduction to the use of aSyn PFFs to generate a rodent model of PD-highlighting phenotypes observed in papers that set out to thoroughly characterize the model. This information will hopefully improve the understanding of this model and clarify when the aSyn PFF model may be an appropriate choice for one's research.
Topics: Animals; Brain; Parkinson Disease; Phenotype; Rodentia; alpha-Synuclein
PubMed: 34486988
DOI: 10.3233/JPD-212847 -
Small GTPases Apr 2017A common pathological event among various neurodegenerative disorders (NDs) is the misfolding and aggregation of different proteins in the brain. This is thought to... (Review)
Review
A common pathological event among various neurodegenerative disorders (NDs) is the misfolding and aggregation of different proteins in the brain. This is thought to potentiate aberrant protein-protein interactions that culminate in the disruption of several biological processes and, ultimately, in neuronal cell loss. Although protein aggregates are a common hallmark in several disorders, the molecular pathways leading to their generation remain unclear. The misfolding and aggregation of α-Synuclein (aSyn) is the pathological hallmark of Parkinson disease (PD), the second most common age related ND. It has been postulated that oligomeric species of aSyn, rather than more mature aggregated forms of the protein, are the causative agents of cytotoxicity. In recent years, we have been investigating the molecular mechanisms underlying the initial steps of aSyn accumulation in living cells. Using an unbiased genome-wide lentiviral RNAi screen we identified trafficking and kinase genes as modulators of aSyn oligomerization, aggregation, and toxicity. Among those, Rab8b, Rab11a, Rab13 and Slp5 were found to promote the clearance of aSyn inclusions and reduce aSyn toxicity. Moreover, we found that endocytic recycling and secretion of aSyn was enhanced upon expression of Rab11a or Rab13 in cells accumulating aSyn inclusions. Altogether, our findings suggest specific trafficking steps may prove beneficial as targets for therapeutic intervention in synucleinopathies, and should be further investigated in other models.
Topics: Animals; Humans; Parkinson Disease; Protein Aggregates; Protein Transport; alpha-Synuclein
PubMed: 27314512
DOI: 10.1080/21541248.2016.1199191 -
Current Neurology and Neuroscience... Sep 2006Expression of the Parkinson's disease-associated protein alpha-synuclein causes formation of aggregates and cytotoxicity in a great diversity of transgenic model... (Review)
Review
Expression of the Parkinson's disease-associated protein alpha-synuclein causes formation of aggregates and cytotoxicity in a great diversity of transgenic model organisms, in the case of Drosophila melanogaster affecting specific dopaminergic neuron clusters. The relative contribution of alpha-synuclein misfolding and phosphorylation for neurodegeneration was elucidated in these systems. In transgenic mice, typical neuropathologic inclusions formed concomitant with behavioral deficits, reminiscent of Parkinson's disease, dementia with Lewy bodies, and multiple system atrophy. Neuronal degeneration was cell-autonomous in the Lewy body disease models, whereas gliotic changes accompanied neurodegeneration caused by (oligodendro)glial cytoplasmic inclusions. These recent findings provided major insights into the molecular mechanisms of alpha-synucleinopathies.
Topics: Animals; Disease Models, Animal; Humans; Mice; Mice, Transgenic; Neurodegenerative Diseases; alpha-Synuclein
PubMed: 16928354
DOI: 10.1007/s11910-996-0025-8