Four of 264 families (1.5%) with typical ADPD carried duplications and 1 of 22 families (4.5%) with atypical AD parkinsonism carried a triplication of SNCA.
The knowledge accumulated thus far has delineated two putative, potentially interconnected, disease-causing pathways: alpha-synuclein accumulation may be central to Parkinsonism due to alpha-synuclein gene defects, but possibly also to sporadic PD and other genetic forms presenting with Lewy bodies; altered mitochondrial physiology may be pivotal to Parkinsonian syndromes caused by parkin, PINK1, and possibly DJ-1 gene mutations.
Alpha-synuclein gene (SNCA) mutations cause familial Parkinsonism but the role of SNCA variability in idiopathic Parkinson's disease (PD) remains incompletely defined.
Herein we characterize five families with parkinsonism that have been identified to harbor multiplication of the chromosomal 4q21 locus containing the alpha-synuclein gene (SNCA).
In a first feasibility study employing a novel ELISA, we found relatively low CSF alphaS concentrations in subjects with parkinsonism linked to synucleinopathy, PD and DLB.
With the discovery of missense and multiplication mutations in the alpha-synuclein gene (SNCA) in familial parkinsonism, Lewy inclusions were found to stain intensely with antibodies raised against the protein.
Herein we characterize five families with parkinsonism that have been identified to harbor multiplication of the chromosomal 4q21 locus containing the alpha-synuclein gene (SNCA).
Pathologically confirmed Lewy body disease clinically characterized by progressive parkinsonism and cognitive dysfunction is caused by SNCA duplication.
Pathologically confirmed Lewy body disease clinically characterized by progressive parkinsonism and cognitive dysfunction is caused by SNCA duplication.
Mutations in five causative genes combined [alpha-Synuclein (SNCA), Parkin, PTEN-induced kinase 1 (PINK1), DJ-1, Leucine-rich repeat kinase 2 (LRRK2)] account for 2-3% of all cases with classical parkinsonism, often clinically indistinguishable from idiopathic Parkinson's disease.
The discoveries of genes related to hereditary forms of parkinsonism (PARK1, PARK2, PARK6, PARK7 and PARK8) have increased our understanding either of distinct subtypes of clinical expression in PD or its etiology.
Since the discovery in 1997 of the first heritable form of parkinsonism that could be linked to a mutation in a single gene, SNCA, many more genetic leads have followed (Parkin, DJ-1, PINK1, LRRK2, to name a few); these have provided us with many molecular clues to better explore the etiology of parkinsonism and have led to the dismantling of many previously held dogmas about Parkinson disease (PD).
The genetic basis for familial parkinsonism is an SNCA-MMRN11 multiplication, but whereas SNCA-MMRN1 duplication in the Swedish proband (Branch J) leads to late-onset autonomic dysfunction and parkinsonism, SNCA-MMRN1 triplication in the Swedish American family (Branch I) leads to early-onset Parkinson disease and dementia.
Genetic variation of the alpha-synuclein gene (SNCA) is known to cause familial parkinsonism, however the role of SNCA variants in sporadic Parkinson's disease (PD) remains elusive.
We show here, in the MPP+ (1-methyl-4-phenylpyridinium ion) cell model of parkinsonism, a time- and dose-dependent increase in the hyperphosphorylation of Tau at pSer396/404 (PHF-1-reactive Tau, p-Tau), concomitant with increased accumulation of alpha-Syn, upon treatment of cells with the neurotoxin.
The presence of alpha-synuclein Lewy body pathology is used to distinguish Parkinson's disease from parkinsonism, for which a broader spectrum of neuropathologies, including tau-immunopositive neurofibrillary tangles and ubiquitin inclusions, might accompany nigral neuronal loss.
We examined 7 patients from a family harboring a novel mutation in the alpha-synuclein gene (E46K) that segregated with a phenotype of parkinsonism and dementia with Lewy bodies.
NMR spectroscopy demonstrates that Parkinsonism-linked mutations greatly perturb specific tertiary interactions essential for the native state of alpha-synuclein.
However, MnCl(2) resulted in a significantly stronger decreased viability of cells overexpressing alpha-synuclein after 72 h. These findings suggest that manganese may co-operate with alpha-synuclein in triggering neuronal cell death such as seen in manganese parkinsonism.