Disease relevance of Snca

• Mutations in the alpha-synuclein (alphaSYN) gene are associated with rare cases of familial Parkinson's disease, and alphaSYN is a major component of Lewy bodies and Lewy neurites [1].
• Distinct alpha-SYN species were detected in the detergent-insoluble fractions from brains of patients with PD, dementia with LBs, and neurodegeneration with brain iron accumulation type 1 (formerly known as Hallervorden-Spatz disease) [2].
• alpha-Synuclein is an abundant presynaptic protein implicated in neuronal plasticity and neurodegenerative diseases [3].
• Developmental loss and resistance to MPTP toxicity of dopaminergic neurones in substantia nigra pars compacta of gamma-synuclein, alpha-synuclein and double alpha/gamma-synuclein null mutant mice [4].
• Mouse model of multiple system atrophy alpha-synuclein expression in oligodendrocytes causes glial and neuronal degeneration [5].
• Our data reveal a molecular link between central pathogenic mechanisms implicated in Parkinson's disease and Alzheimer's disease and suggest that intracellular alpha-synuclein is pathogenic, at least in part, by activation of extracellular signaling pathways involving ApoE [6].

Psychiatry related information on Snca

• Expression pattern of synucleins (non-Abeta component of Alzheimer's disease amyloid precursor protein/alpha-synuclein) during murine brain development [7].
• In mice lacking alpha-synuclein, continuous MPTP delivery still induced metabolic activation, but induction of behavioral symptoms and neuronal cell death were almost completely alleviated [8].
• We show here that the absence of alpha-synuclein resulting from spontaneous mutation in a subline of C57BL/6J mice greatly increased the rate of operant behavior during intracranial self-stimulation [9].
• The present work demonstrates that a lack of alpha-synuclein sensitized the brain reward system, implying that the levels of alpha-synuclein expression may predispose an individual to drug abuse or to a number of psychiatric diseases [9].

High impact information on Snca

• These results suggest that accumulation of wild-type alpha-synuclein may play a causal role in Parkinson's disease and related conditions [10].
• Dopaminergic loss and inclusion body formation in alpha-synuclein mice: implications for neurodegenerative disorders [10].
• Neuronal expression of human alpha-synuclein resulted in progressive accumulation of alpha-synuclein-and ubiquitin-immunoreactive inclusions in neurons in the neocortex, hippocampus, and substantia nigra [10].
• Our studies demonstrate that overexpression of alpha-synuclein in oligodendrocytes of mice results in MSA-like degeneration in the CNS and that alpha-synuclein inclusions in oligodendrocytes participate in the degeneration of neurons in MSA [5].
• Neuronal alpha-synucleinopathy with severe movement disorder in mice expressing A53T human alpha-synuclein [11].

Chemical compound and disease context of Snca

• Role of alpha-synuclein in 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine-induced parkinsonism in mice [12].
• Presynaptic depression of evoked EPSCs by hypoxia or adenosine was significantly larger in alpha-Syn knockout than in wild-type mice, further supporting the hypothesis of regulation of synaptic transmission by alpha-Syn [13].
• One of the models for which parkin is protective is overexpression of alpha-synuclein, a protein that self-aggregates in Parkinson disease [14].
• We have recently shown that Abeta and alpha-synuclein, associated with Alzheimer's disease, Parkinson's disease and related disorders, can both induce the formation of hydroxyl radicals following incubation in solution, upon addition of Fe(II) [15].
• Despite attenuated toxicity, elevated lactate concentrations were observed in alpha-synuclein knock-out mice following prolonged, chronic MPTP administration [16].

Biological context of Snca

• Thus, altered membrane composition and structure and impaired complex I/III function in Snca-/- brain suggest a relationship between alpha-synuclein's role in brain lipid metabolism, mitochondrial function, and PD [17].
• Herein, we report a mechanism by which alpha-synuclein diminishes tyrosine hydroxylase phosphorylation and activity in stably transfected dopaminergic cells [3].
• Despite the lack of alpha-synuclein and multimerin-1 C57BL/6JOlaHsd animals do not display obvious phenotypes [18].
• The present study examines whether alpha-synuclein deficiency in neurons alters their sensitivity to proteasomal inhibition-induced apoptosis or inclusion formation [19].
• This was caused by a chromosomal deletion of the alpha-synuclein locus in the C57BL/6J inbred strain used for backcrossing [20].

Anatomical context of Snca

• Subcellular fractionation of mouse brain revealed that both alphaSYN and betaSYN were present in synaptosomes [1].
• Selective insolubility of alpha-synuclein in human Lewy body diseases is recapitulated in a transgenic mouse model [2].
• Synphilin-1 is known to interact with alpha-synuclein, promoting the formation of cytoplasmic inclusions like Lewy bodies in vitro [21].
• Double immunofluorescent staining showed that alpha-synuclein and synphilin-1 or 14-3-3 proteins were colocalized in the pons and spinal cord [21].
• In homozygous mouse brains, alpha-synuclein immunoreactivity was observed in the neuronal somata and processes in the medial part of the brainstem, deep cerebellar nuclei, and spinal cord [21].

Associations of Snca with chemical compounds

• In mice lacking alpha-synuclein (Snca-/-), total brain steady-state mass of the mitochondria-specific phospholipid, cardiolipin, is reduced 22% and its acyl side chains show a 51% increase in saturated FAs and a 25% reduction in essential n-6, but not n-3, polyunsaturated FAs [17].
• Although the function of alpha-synuclein is not thoroughly elucidated, we found that alpha-synuclein regulates dopamine synthesis by binding to and inhibiting tyrosine hydroxylase, the rate limiting enzyme in dopamine synthesis [3].
• However, tyrosine administration did not enhance phosphorylated TH levels or enzyme catalytic activity in raclopride-stimulated NSDA neurons in alpha-synuclein knockout mice [22].
• There was no difference in phosphorylated TH levels or TH catalytic activity between wild-type and alpha-synuclein knockout mice under basal conditions or following raclopride-induced acceleration of NSDA activity [22].
• In contrast, however, ubiquitinated inclusions in alpha-synuclein-deficient neurons lacked amyloid-like fibrillization, as determined by thioflavine S staining [19].

Physical interactions of Snca

• These results demonstrate that alpha-synuclein is not obligatorily coupled to MPTP sensitivity, but can influence MPTP toxicity on some genetic backgrounds, and illustrate the need for extensive controls in studies aimed at describing the effects of mouse knockouts on MPTP sensitivity [12].

Co-localisations of Snca

• alpha-Synuclein is colocalized with 14-3-3 and synphilin-1 in A53T transgenic mice [21].

Regulatory relationships of Snca

• Haploinsufficiency for trkB and trkC receptors induces cell loss and accumulation of alpha-synuclein in the substantia nigra [23].
• beta-amyloid peptides enhance alpha-synuclein accumulation and neuronal deficits in a transgenic mouse model linking Alzheimer's disease and Parkinson's disease [24].

Other interactions of Snca

• The present study supports the hypothesis that alpha-synuclein functions as a molecular chaperone protein that regulates the phosphorylation state of TH in a substrate and activity-dependent manner [22].
• Deletion of multimerin-1 in alpha-synuclein-deficient mice [18].
• The distribution of 14-3-3 proteins and synphilin-1 immunoreactivity was similar to that of alpha-synuclein in the homozygous mice [21].
• Unexpected Rescue of Alpha-synuclein and Multimerin1 Deletion in C57BL/6JOlaHsd Mice by Beta-adducin Knockout [25].
• Lack of alpha-synuclein increases amyloid plaque accumulation in a transgenic mouse model of Alzheimer's disease [26].

Analytical, diagnostic and therapeutic context of Snca

• Synaptic colocalization of alphaSYN and betaSYN was directly visualized by confocal microscopy of double-stained human brain sections [1].
• To understand better the patterns of NACP expression during development, we analyzed the levels of this protein as well as the levels of another synaptic protein (synaptophysin) by ribonuclease protection assay, western blotting, and immunocytochemistry in fetal, juvenile, and adult mouse brain [7].
• RESULTS: Expression profiling by cDNA array technology in a transgenic mouse model revealed striking differences only in the expression level of alpha-synuclein [20].
• Moreover, immunoelectron microscopy revealed that the alpha-synuclein inclusions contained 10-16 nm wide fibrils similar to human pathological inclusions [11].
• Nigrostriatal terminals of alpha-Syn-/- mice display a standard pattern of dopamine (DA) discharge and reuptake in response to simple electrical stimulation [27].

References