Nuclear localization and phosphorylation modulate pathological effects of alpha-synuclein.

Alpha-synuclein (aSyn) is a central player in Parkinson's disease (PD) but the precise molecular mechanisms underlying its pathogenicity remain unclear. It has recently been suggested that nuclear aSyn may modulate gene expression, possibly via interactions with DNA. However, the biological behavior of aSyn in the nucleus and the factors affecting its transcriptional role are not known.

Membrane binding, internalization, and sorting of alpha-synuclein in the cell.

Alpha-synuclein (aSyn) plays a crucial role in Parkinson's disease (PD) and other synucleinopathies, since it misfolds and accumulates in typical proteinaceous inclusions. While the function of aSyn is thought to be related to vesicle binding and trafficking, the precise molecular mechanisms linking aSyn with synucleinopathies are still obscure. aSyn can spread in a prion-like manner between interconnected neurons, contributing to the propagation of the pathology and to the progressive nature of synucleinopathies.

Environmental and genetic factors support the dissociation between α-synuclein aggregation and toxicity.

Synucleinopathies are a group of progressive disorders characterized by the abnormal aggregation and accumulation of α-synuclein (aSyn), an abundant neuronal protein that can adopt different conformations and biological properties. Recently, aSyn pathology was shown to spread between neurons in a prion-like manner. Proteins like aSyn that exhibit self-propagating capacity appear to be able to adopt different stable conformational states, known as protein strains, which can be modulated both by environmental and by protein-intrinsic factors.

A familial ATP13A2 mutation enhances alpha-synuclein aggregation and promotes cell death.

Aberrant protein-protein interactions are a common pathological hallmark among neurodegenerative diseases, including Parkinson's disease (PD). Thus far, mutations in more than 20 genes have been associated with PD. These genes encode for proteins involved in distinct intracellular pathways, complicating our understanding of the precise molecular mechanisms underlying the disease.

Fasudil attenuates aggregation of α-synuclein in models of Parkinson's disease.

Parkinson's disease (PD) is the most common neurodegenerative movement disorder, yet disease-modifying treatments do not currently exist. Rho-associated protein kinase (ROCK) was recently described as a novel neuroprotective target in PD. Since alpha-synuclein (α-Syn) aggregation is a major hallmark in the pathogenesis of PD, we aimed to evaluate the anti-aggregative potential of pharmacological ROCK inhibition using the isoquinoline derivative Fasudil, a small molecule inhibitor already approved for clinical use in humans.

Cellular Uptake of α-Synuclein Oligomer-Selective Antibodies is Enhanced by the Extracellular Presence of α-Synuclein and Mediated via Fcγ Receptors.

Immunotherapy targeting aggregated α-synuclein has emerged as a potential treatment strategy against Parkinson's disease and other α-synucleinopathies. We have developed α-synuclein oligomer/protofibril selective antibodies that reduce toxic α-synuclein in a human cell line and, upon intraperitoneal administration, in spinal cord of transgenic mice. Here, we investigated under which conditions and by which mechanisms such antibodies can be internalized by cells.

Structure, function and toxicity of alpha-synuclein: the Bermuda triangle in synucleinopathies.

Parkinson's disease belongs to a group of currently incurable neurodegenerative disorders characterized by the misfolding and accumulation of alpha-synuclein aggregates that are commonly known as synucleinopathies. Clinically, synucleinopathies are heterogeneous, reflecting the somewhat selective neuronal vulnerability characteristic of each disease. The precise molecular underpinnings of synucleinopathies remain unclear, but the process of aggregation of alpha-synuclein appears as a central event.

LRRK2 Promotes Tau Accumulation, Aggregation and Release.

Mutations in the leucine-rich repeat kinase 2 (LRRK2) gene are known as the most frequent cause of familial Parkinson's disease (PD), but are also present in sporadic cases. The G2019S-LRRK2 mutation is located in the kinase domain of the protein, and has consistently been reported to promote a gain of kinase function. Several proteins have been reported as LRRK2 substrates and/or interactors, suggesting possible pathways involved in neurodegeneration in PD.

The Interplay between Alpha-Synuclein Clearance and Spreading.

Parkinson's Disease (PD) is a complex neurodegenerative disorder classically characterized by movement impairment. Pathologically, the most striking features of PD are the loss of dopaminergic neurons and the presence of intraneuronal protein inclusions primarily composed of alpha-synuclein (α-syn) that are known as Lewy bodies and Lewy neurites in surviving neurons. Though the mechanisms underlying the progression of PD pathology are unclear, accumulating evidence suggests a prion-like spreading of α-syn pathology.

ATP13A2 and Alpha-synuclein: a Metal Taste in Autophagy.

Parkinson's Disease (PD) is a complex and multifactorial disorder of both idiopathic and genetic origin. Thus far, more than 20 genes have been linked to familial forms of PD. Two of these genes encode for ATP13A2 and alpha-synuclein (asyn), proteins that seem to be members of a common network in both physiological and disease conditions.

α-Synuclein interacts with the switch region of Rab8a in a Ser129 phosphorylation-dependent manner.

Alpha-synuclein (αS) misfolding is associated with Parkinson's disease (PD) but little is known about the mechanisms underlying αS toxicity. Increasing evidence suggests that defects in membrane transport play an important role in neuronal dysfunction. Here we demonstrate that the GTPase Rab8a interacts with αS in rodent brain.

The zebrafish homologue of Parkinson's disease ATP13A2 is essential for embryonic survival.

ATP13A2 is a lysosome-specific transmembrane ATPase protein of unknown function. This protein was initially linked to Kufor-Rakeb syndrome where it is absent or mutated. More recently, point mutations in ATP13A2 were linked to familial cases of Parkinson's disease.