Aggregation of α-Synuclein in S. cerevisiae is Associated with Defects in Endosomal Trafficking and Phospholipid Biosynthesis

Parkinson’s disease is the most common neuro-degenerative movement disorder. α-Synuclein is a small synaptic protein that has been linked to familial Parkinson’s disease (PD) and is also the primary component of Lewy bodies, the hallmark neuropathology found in the brain of sporadic and familial PD patients. The function of α-synuclein is currently unknown, although it has been implicated in the regulation of synaptic vesicle localization or fusion. Recently, overexpression of α-synuclein was shown to cause cytoplasmic vesicle accumulation in a yeast model of α-synuclein toxicity, but the exact role α-synuclein played in mediating this vesicle aggregation is unclear. Here, we show that α-synuclein induces aggregation of many yeast Rab GTPase proteins, that α-synuclein aggregation is enhanced in yeast mutants that produce high levels of acidic phospholipids, and that α-synuclein colocalizes with yeast membranes that are enriched for phosphatidic acid. Significantly, we demonstrate that α-synuclein expression induces vulnerability to perturbations of Ypt6 and other proteins involved in retrograde endosome–Golgi transport, linking a specific trafficking defect to α-synuclein phospholipid binding. These data suggest new pathogenic mechanisms for α-synuclein neurotoxicity

Corporate governance in Colombian universities

Abstract In a context of greater demands in terms of accountability and transparency in management, we analyse the extent to which Corporate Governance (CG) mechanisms have been adopted and we define the model of governance in universities in Colombia. In the field of higher education, there are usually no compulsory requirements related to CG. Nevertheless, governance mechanisms are nowadays crucial in determining the objectives, strategies and direction of universities. Based on a survey of 81 rectors of higher education institutions in Colombia, we analyse the models of CG adopted (managerial and stakeholder models). The results contribute to a better understanding of key CG concepts at universities. Points for practitioners There is an increasing awareness of the importance of improving the mechanisms of governance that may help to achieve greater effectiveness and efficiency in the management of resources and awareness of society. The analysis of the predominant CG models, the stakeholder model and the managerial model, and the way in which Colombian universities are introducing these models could be used to promote the establishment of a common legal framework. This model should be flexible and include different opinions and preferences. The results may be useful and could be transferred to other countries that have the same characteristics

Molecular and Biological Compatibility with Host Alpha-Synuclein Influences Fibril Pathogenicity

The accumulation and propagation of misfolded α-synuclein (α-Syn) is a central feature of Parkinson’s disease and other synucleinopathies. Molecular compatibility between a fibrillar seed and its native protein state is a major determinant of amyloid self-replication. We show that cross-seeded aggregation of human (Hu) and mouse (Ms) α-Syn is bidirectionally restricted. Although fibrils formed by Hu-Ms-α-Syn chimeric mutants can overcome this inhibition in cell-free systems, sequence homology poorly predicts their efficiency in inducing α-Syn pathology in primary neurons or after intracerebral injection into wild-type mice. Chimeric α-Syn fibrils demonstrate enhanced or reduced pathogenicities compared with wild-type Hu- or Ms-α-Syn fibrils. Furthermore, α-Syn mutants induced to polymerize by fibrillar seeds inherit the functional properties of their template, suggesting that transferable pathogenic and non-pathogenic states likely influence the initial engagement between exogenous α-Syn seeds and endogenous neuronal α-Syn. Thus, transmission of synucleinopathies is regulated by biological processes in addition to molecular compatibility

Aggregation of α-Synuclein in S. cerevisiae is Associated with Defects in Endosomal Trafficking and Phospholipid Biosynthesis

Parkinson’s disease is the most common neuro-degenerative movement disorder. α-Synuclein is a small synaptic protein that has been linked to familial Parkinson’s disease (PD) and is also the primary component of Lewy bodies, the hallmark neuropathology found in the brain of sporadic and familial PD patients. The function of α-synuclein is currently unknown, although it has been implicated in the regulation of synaptic vesicle localization or fusion. Recently, overexpression of α-synuclein was shown to cause cytoplasmic vesicle accumulation in a yeast model of α-synuclein toxicity, but the exact role α-synuclein played in mediating this vesicle aggregation is unclear. Here, we show that α-synuclein induces aggregation of many yeast Rab GTPase proteins, that α-synuclein aggregation is enhanced in yeast mutants that produce high levels of acidic phospholipids, and that α-synuclein colocalizes with yeast membranes that are enriched for phosphatidic acid. Significantly, we demonstrate that α-synuclein expression induces vulnerability to perturbations of Ypt6 and other proteins involved in retrograde endosome–Golgi transport, linking a specific trafficking defect to α-synuclein phospholipid binding. These data suggest new pathogenic mechanisms for α-synuclein neurotoxicity