We briefly discuss some of the lessons we have learned from research into the physiological role of α-synuclein and its pathological links to neurodegeneration and parkinsonism.
Ample evidence has suggested that extracellular α-synuclein aggregates would play key roles in the pathogenesis and progression of Parkinsonian disorders (PDs).
In addition, NCGC607 reduced α-synuclein levels in dopaminergic neurons from the patients with parkinsonism, suggesting that noninhibitory small-molecule chaperones of glucocerebrosidase may prove useful for the treatment of Parkinson disease.
An analysis of 43 tagging single nucleotide polymorphisms across the SNCA locus shows 2 distinct association profiles for symptoms of parkinsonism and/or dementia, respectively, toward the 3' or the 5' of the SNCA gene.
Methylmercury can induce Parkinson's-like neurotoxicity similar to 1-methyl-4- phenylpyridinium: a genomic and proteomic analysis on MN9D dopaminergic neuron cells.
We found that over half of the reported cases with SNCA duplication had early-onset parkinsonism and non-motor features, such as dysautonomia, rapid eye movement sleep behavior disorder (RBD), hallucinations (usually visual) and cognitive deficits leading to dementia.
MSA is a slowly evolving disorder characterized by progressive loss of autonomic nervous system function and often signs of parkinsonism; the neuropathological hallmark of MSA is glial cytoplasmic inclusions consisting of filaments of α-synuclein.
The SNCA duplication case presented with a clinical phenotype of frontotemporal dementia with marked behavioural changes, pyramidal signs, postural hypotension and transiently levodopa responsive parkinsonism.
The patients carrying the SNCA triplication developed early-onset parkinsonism combined with depression, behavior disturbances, sleep disorders, and cognitive decline; marked autonomic dysfunctions were not observed.
There appears to be four common processes linking the two disorders, as mutations in genes associated with Parkinsonism initiate similar adverse biological reactions acknowledged to stimulate Mn-induced dopaminergic cell death including; (1) disruption of mitochondrial function leading to oxidative stress, (2) abnormalities in vesicle processing, (3) altered proteasomal and lysosomal protein degradation, and (4) α-synuclein aggregation The mutual neurotoxic processes provoked by mutations in these genes in concert with the biological disturbances produced by Mn, most likely, act in synchrony to contribute to the severity, characteristics and onset of both disorders.
Specifically, mice overexpressing human wild-type aSyn under a broad neuronal promoter (Thy1-aSyn) present early, progressive motor and nonmotor deficits starting at 2-3 months, followed by parkinsonism with dopamine loss at 14 months.
Our results suggest that the novel SNCAA53E substitution is a causative mutation resulting clinically in parkinsonism and pathologically in severe multiple system atrophy- and PD-type phenotype.
α-Synuclein gene (SNCA) multiplications cause familial parkinsonism and allele-length polymorphisms within the SNCA dinucleotide repeat REP1 increase the risk for developing Parkinson's disease (PD).
In vivo electrophysiology of nigral and thalamic neurons in alpha-synuclein-overexpressing mice highlights differences from toxin-based models of parkinsonism.
Understanding the clinical association between GBA and PD, and the relationship between ß-glucocerebrosidase and α-synuclein, may enhance understanding of the pathogenesis of IPD, improve prognostication and treatment of GBA carriers with parkinsonism, and furthermore inform therapies for IPD not due to GBA mutations.