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.
Parkinsonism-linked mutations in alanine and glutamic acid residues of the pre-synaptic protein α-Synuclein (α-Syn) affect specific tertiary interactions essential for stability of the native state and make it prone to more aggregation.
The fact that Lewy bodies stain strongly with antibodies to asynuclein and that mutations in the alpha-synuclein gene lead to syndromes in which parkinsonism and dementia occur gives us important clues regarding the biologic processes leading to disease.
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.
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.
Synucleinopathies are a spectrum of neurodegenerative diseases characterized by the intracellular deposition of the protein α-synuclein leading to multiple outcomes, including dementia and Parkinsonism.
Multiple system atrophy (MSA) is a rare neurodegenerative disease of undetermined cause manifesting with progressive autonomic failure (AF), cerebellar ataxia and parkinsonism due to neuronal loss in multiple brain areas associated with (oligodendro)glial cytoplasmic alpha-synuclein (alpha SYN) inclusions (GCIs).
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.
Mutations in the alpha-synuclein (alpha-syn) gene are responsible for a rare familial parkinsonism syndrome, a finding that has led to extensive characterization of altered alpha-syn structure in sporadic Parkinson's disease (PD) and other neurodegenerative disorders.
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.
Furthermore, studies in singly and doubly tg mice have shown that toxic conversion and accumulation can be accelerated by alpha-synuclein mutations associated with familial parkinsonism, by amyloid beta peptide 1-42 (Abeta 1-42), and by oxidative stress.