Defining the causes of sporadic Parkinson's disease in the global Parkinson's genetics program (GP2)

The Global Parkinson’s Genetics Program (GP2) will genotype over 150,000 participants from around the world, and integrate genetic and clinical data for use in large-scale analyses to dramatically expand our understanding of the genetic architecture of PD. This report details the workflow for cohort integration into the complex arm of GP2, and together with our outline of the monogenic hub in a companion paper, provides a generalizable blueprint for establishing large scale collaborative research consortia

Multi-ancestry genome-wide association meta-analysis of Parkinson?s disease

Although over 90 independent risk variants have been identified for Parkinson’s disease using genome-wide association studies, most studies have been performed in just one population at a time. Here we performed a large-scale multi-ancestry meta-analysis of Parkinson’s disease with 49,049 cases, 18,785 proxy cases and 2,458,063 controls including individuals of European, East Asian, Latin American and African ancestry. In a meta-analysis, we identified 78 independent genome-wide significant loci, including 12 potentially novel loci (MTF2, PIK3CA, ADD1, SYBU, IRS2, USP8, PIGL, FASN, MYLK2, USP25, EP300 and PPP6R2) and fine-mapped 6 putative causal variants at 6 known PD loci. By combining our results with publicly available eQTL data, we identified 25 putative risk genes in these novel loci whose expression is associated with PD risk. This work lays the groundwork for future efforts aimed at identifying PD loci in non-European populations

Rational Knob-Socket Predictions of Alpha-Helical Stability

A construct that simplifies the complexity of residue packing would significantly impact our understanding and analysis higher order protein structure in the same way that the covalent peptide bond allows linear comparisons of protein sequences and main-chain hydrogen bonding patterns identify secondary structure. The novel knob-socket (KS) model provides a construct to interpret and analyze the direct contributions of amino acid residues to the stability in α-helical protein structures. Based on residue preferences derived from a set of protein structures, the KS construct characterizes intra- and inter-helical packing into regular patterns of simple motifs. Intra-helical interactions consist of a regular pattern of three residue triangular motifs called sockets, which contribute to helical stability. For inter-helical interactions, a single amino acid knob from one α-helix packs into a three amino acid socket within another α-helix. Therefore, sockets are defined in three categories: (1) free, unpacked and favoring intra-helical interactions, (2) filled, packed and favoring inter-helical interactions, and (3) non, unpacked and disfavoring α-helical structure. The three amino acid composition of a socket serves as a code that can be used to predict protein packing and by extension, can also be used to understand individual amino acid contributions to helical stability. The KS model was used in the de novo design of an α-helical homodimer, KSα1.1. Using site-directed mutagenesis, KSα1.1 point mutants have been rationally chosen to increase and decrease stability by relating KS propensities with changes to α-helical structure. In the KS α-helical model, each point mutation affects six surrounding sockets by altering the free/filled propensity values. By analyzing the changes in the propensities of these six sockets, KS based structure predictions were made for each mutant that relate to their stability. These predicted values are compared to the experimentally determined structure and stability of each protein from chemical and thermal denaturation studies as measured by circular dichroism spectroscopy. This study serves as a starting point to reveal how residue packing contributes to protein stability

Investigating the Specificity of Coiled Coil Recognition

bZIP transcription factors make up a family of long α-helical proteins that dimerize and bind to DNA through a basic region that contains hydrophobic residues. They function as gene expression regulating factors and are therefore attractive possible candidates for small molecule binding. Binding specificity is a particular topic of interest. The development of an accurate method to characterize and map out the binding specificity of these bZIP proteins, would enable us to alter and possibly inhibit the function of its protein interactions. Use of the Knob-Socket model for determination of packing structure provides a novel approach to analyze protein-protein as well as protein-nucleic acid interactions. A Knob-Socket analysis of the protein-protein interface provides unique insight into the classical leucine zipper pseudo-7mer repeat. A deeper analysis of longer leucine zippers shows unique packing patterns not indicated by classical representations like the helical wheel. From analysis of the Knob-Socket packing maps, this research provides evidence of a general framework for defining the specificity between coiled coils. the Knob-Socket maps show how hydrophobic specificity is defined in the coiled coil interface, where knobs are centralized in the middle of the socket packing, while the peripheral socket residues are hydrophilic. Furthermore, the bias of the filled over free propensities shows a clear pattern that explains the specificity of a set of hydrophobic interactions

Rational Knob-Socket Predictions of Alpha-Helical Stability

A construct that simplifies the complexity of residue packing would significantly impact our understanding and analysis higher order protein structure in the same way that the covalent peptide bond allows linear comparisons of protein sequences and main-chain hydrogen bonding patterns identify secondary structure. The novel knob-socket (KS) model provides a construct to interpret and analyze the direct contributions of amino acid residues to the stability in α-helical protein structures. Based on residue preferences derived from a set of protein structures, the KS construct characterizes intra- and inter-helical packing into regular patterns of simple motifs. Intra-helical interactions consist of a regular pattern of three residue triangular motifs called sockets, which contribute to helical stability. For inter-helical interactions, a single amino acid knob from one α-helix packs into a three amino acid socket within another α-helix. Therefore, sockets are defined in three categories: (1) free, unpacked and favoring intra-helical interactions, (2) filled, packed and favoring inter-helical interactions, and (3) non, unpacked and disfavoring α-helical structure. The three amino acid composition of a socket serves as a code that can be used to predict protein packing and by extension, can also be used to understand individual amino acid contributions to helical stability. The KS model was used in the de novo design of an α-helical homodimer, KSα1.1. Using site-directed mutagenesis, KSα1.1 point mutants have been rationally chosen to increase and decrease stability by relating KS propensities with changes to α-helical structure. In the KS α-helical model, each point mutation affects six surrounding sockets by altering the free/filled propensity values. By analyzing the changes in the propensities of these six sockets, KS based structure predictions were made for each mutant that relate to their stability. These predicted values are compared to the experimentally determined structure and stability of each protein from chemical and thermal denaturation studies as measured by circular dichroism spectroscopy. This study serves as a starting point to reveal how residue packing contributes to protein stability

Investigating the Specificity of Coiled Coil Recognition

bZIP transcription factors make up a family of long α-helical proteins that dimerize and bind to DNA through a basic region that contains hydrophobic residues. They function as gene expression regulating factors and are therefore attractive possible candidates for small molecule binding. Binding specificity is a particular topic of interest. The development of an accurate method to characterize and map out the binding specificity of these bZIP proteins, would enable us to alter and possibly inhibit the function of its protein interactions. Use of the Knob-Socket model for determination of packing structure provides a novel approach to analyze protein-protein as well as protein-nucleic acid interactions. A Knob-Socket analysis of the protein-protein interface provides unique insight into the classical leucine zipper pseudo-7mer repeat. A deeper analysis of longer leucine zippers shows unique packing patterns not indicated by classical representations like the helical wheel. From analysis of the Knob-Socket packing maps, this research provides evidence of a general framework for defining the specificity between coiled coils. the Knob-Socket maps show how hydrophobic specificity is defined in the coiled coil interface, where knobs are centralized in the middle of the socket packing, while the peripheral socket residues are hydrophilic. Furthermore, the bias of the filled over free propensities shows a clear pattern that explains the specificity of a set of hydrophobic interactions

Exploration of trans-2-(1,2,3-triazolyl)-cyclohexanols as potential inhibitors for fungal glycosidases

A series of carbasugars based on trans-2-(1,2,3-triazolyl)-cyclohexanol moiety was synthesized for the first time by a “click reaction” of the corresponding azides and alkynes, and tested for the inhibitory activity towards fungal glycosidases from Aspergillus and Penicillium sp

Exploration of trans-2-(1,2,3-triazolyl)-cyclohexanols as potential inhibitors for fungal glycosidases

A series of carbasugars based on trans-2-(1,2,3-triazolyl)-cyclohexanol moiety was synthesized for the first time by a “click reaction” of the corresponding azides and alkynes, and tested for the inhibitory activity towards fungal glycosidases from Aspergillus and Penicillium sp

Defining the causes of sporadic Parkinson’s disease in the global Parkinson’s genetics program (GP2)

The Global Parkinson’s Genetics Program (GP2) will genotype over 150,000 participants from around the world, and integrate genetic and clinical data for use in large-scale analyses to dramatically expand our understanding of the genetic architecture of PD. This report details the workflow for cohort integration into the complex arm of GP2, and together with our outline of the monogenic hub in a companion paper, provides a generalizable blueprint for establishing large scale collaborative research consortia

Multi-ancestry genome-wide association meta-analysis of Parkinson’s disease

Although over 90 independent risk variants have been identified for Parkinson’s disease using genome-wide association studies, most studies have been performed in just one population at a time. Here we performed a large-scale multi-ancestry meta-analysis of Parkinson’s disease with 49,049 cases, 18,785 proxy cases and 2,458,063 controls including individuals of European, East Asian, Latin American and African ancestry. In a meta-analysis, we identified 78 independent genome-wide significant loci, including 12 potentially novel loci (MTF2, PIK3CA, ADD1, SYBU, IRS2, USP8, PIGL, FASN, MYLK2, USP25, EP300 and PPP6R2) and fine-mapped 6 putative causal variants at 6 known PD loci. By combining our results with publicly available eQTL data, we identified 25 putative risk genes in these novel loci whose expression is associated with PD risk. This work lays the groundwork for future efforts aimed at identifying PD loci in non-European populations