Implicated in neurotoxicity are two alphaSN mutants (A53T and A30P) that cause extremely rare familial forms of PD, alphaSN fibrils and protofibrils, soluble protein complexes of alphaSN with 14-3-3 protein, and phosphorylated, nitrosylated, and ubiquitylated alphaSN species.
Based on these results, the alphaSN overexpressing cell lines may represent a good and effective in vitro model for Alzheimer's and Parkinson's disease.
Autophagy is a key clearance pathway involved in the removal of such proteins, including mutant huntingtin (that causes Huntington's disease), mutant ataxin-3 (that causes spinocerebellar ataxia type 3), forms of tau that cause tauopathies, and forms of alpha-synuclein that cause familial Parkinson's disease.
We also critically discuss the contribution and relevance of protein aggregation, namely of α-synuclein and tau-proteins, which are known to form aggregates in PD brains harboring <i>LRRK2</i> mutations, to neurodegeneration in LRRK2 rodent models.
These findings reveal a novel gain of toxic function of alpha-synuclein at the synapse, which may be an early event in the pathogenesis of Parkinson's disease.
They further show that oxidative stress augments cell-cell transfer of α-Syn, which may be an important mechanism underlying the development and progression of PD.
We also assessed the relationship between αSyn deposits and mitochondria in brain tissue from patients with PLA2G6-associated neurodegeneration (PLAN) and Parkinson's disease (PD), and quantitatively examined Lewy bodies (LBs) and neurons.
These results suggest that L-DOPA may slow the progression of PD <i>in vivo</i> by suppressing the aggregation of α-synuclein in dopaminergic neurons and the cell-to-cell propagation of abnormal α-synuclein.
While an Ala53Thr mutation in alpha-synuclein can cause PD in humans, in mice the wildtype residue at position 53 is threonine, indicating that mice are either too short-lived to develop PD, or are protected by the six other amino acid differences between the proteins in these two species.
The frequency of SNCArs356182-G allele was significantly higher in PD group than that in controls (odds ratio (OR)=1.470, 95% confidence interval (CI): 1.284-1.683, P=2.306E-8).
Further, we present the evidence linking LRRK2 to various possible pathogenic mechanism of PD such as α-synuclein, tau, inflammatory response, oxidative stress, mitochondrial dysfunction, synaptic dysfunction as well as autophagy-lysosomal system.
Hsp70 regulates α-Synuclein (α-Syn) degeneration in Parkinson's disease (PD), indicating that Hsp70 promotion may be able to prevent or reverse α-Syn-induced toxicity in PD.
Such innovative treatment would reduce α-Syn accumulation in the Lewy bodies and preserve remaining neurons yet viable at the time of diagnosis, thus slowing disease progression from the early phase of PD characterized by a relatively mild motor impairment to an advanced and more disabling stage.
Survivors of blast-induced traumatic brain injury (bTBI) have increased susceptibility to Parkinson's disease (PD), characterized by α-synuclein aggregation and the progressive degeneration of nigrostriatal dopaminergic neurons.
Deposits of amyloid fibrils of α-synuclein are the histological hallmarks of Parkinson's disease, dementia with Lewy bodies and multiple system atrophy, with hereditary mutations in α-synuclein linked to the first two of these conditions.
The aim of this study was to determine RBD specific genetic features associated to an increased risk of progression to PD, by sequencing of the SNCA-3'UTR in patients with "idiopathic" RBD (iRBD) and in patients with PD.
Our results indicate that the association of LRRK2 p.R1398H with Parkinson's disease is independent of SNCA and MAPT variants, and vice versa, in Caucasian and Asian populations.
Animal models that accurately recapitulate the accumulation of alpha-synuclein (α-syn) inclusions, progressive neurodegeneration of the nigrostriatal system and motor deficits can be useful tools for Parkinson's disease (PD) research.