The role and precise function of α-synculein in Parkinson disease is still shrouded in mystery. In yeast cells and in neurons, α-synculein accumulation is cytotoxic, but little is known about its normal function or pathobiology. Small GTPases of the Ypt/Rab family are involved in the regulation of vesicular transport. Cycling between the GDP- and GTP-bound forms and the accessory proteins that regulate this cycling are thought to be crucial for Ypt/Rab function. Guanine nucleotide exchange factors (GEFs) stimulate both GDP loss and GTP uptake, and GTPase-activating proteins (GAPs) stimulate GTP hydrolysis. Little is known about GEFs and GAPs for Ypt/Rab proteins. The GEF and GAP activities for Ypt1p localize to particulate cellular fractions. However, contrary to the predictions of current models, the GEF activity localizes to the fraction that functions as the acceptor in an endoplasmic reticulum-to-Golgi transport assay, whereas the GAP activity cofractionates with markers for the donor. Currently in this paper, the authors have discussed that the earliest defect following...  Read more

The role and precise function of α-synculein in Parkinson disease is still shrouded in mystery. In yeast cells and in neurons, α-synculein accumulation is cytotoxic, but little is known about its normal function or pathobiology. Small GTPases of the Ypt/Rab family are involved in the regulation of vesicular transport. Cycling between the GDP- and GTP-bound forms and the accessory proteins that regulate this cycling are thought to be crucial for Ypt/Rab function. Guanine nucleotide exchange factors (GEFs) stimulate both GDP loss and GTP uptake, and GTPase-activating proteins (GAPs) stimulate GTP hydrolysis. Little is known about GEFs and GAPs for Ypt/Rab proteins. The GEF and GAP activities for Ypt1p localize to particulate cellular fractions. However, contrary to the predictions of current models, the GEF activity localizes to the fraction that functions as the acceptor in an endoplasmic reticulum-to-Golgi transport assay, whereas the GAP activity cofractionates with markers for the donor. Currently in this paper, the authors have discussed that the earliest defect following α-synculein expression in yeast was a block in endoplasmic reticulum to Golgi vesicular trafficking. In a genome-wide screen, the largest class of toxicity modifiers were proteins functioning at this same step, including the Rab GTPase Ypt1p, which associated with cytoplasmic α-synculein inclusions. Elevated expression of Rab1, the mammalian Ypt1 homolog, protected against α-synculein-induced dopaminergic neuron loss in animal models of PD. Hence the results discussed in this article are more consistent with a role for Ypt1/Rab proteins in determining the directionality or fidelity of protein sorting and also open up new directions in understanding the role of α-synculein function and the factors that renders in regulating this process.

References:
Jedd G, Richardson C, Litt R, Segev N. The Ypt1 GTPase is essential for the first two steps of the yeast secretory pathway. J Cell Biol. 1995 Nov;131(3):583-90. Abstract

Jones S, Richardson CJ, Litt RJ, Segev N. Identification of regulators for Ypt1 GTPase nucleotide cycling. Mol Biol Cell. 1998 Oct;9(10):2819-37. Abstract

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