Cellular processes associated with LRRK2 function and dysfunction.

Mutations in the leucine-rich repeat kinase 2 (LRRK2) encoding gene are the most common cause of monogenic Parkinson's Disease (PD). The identification of LRRK2 polymorphisms associated with increased risk for sporadic PD, as well as the observation that LRRK2-PD has an almost indistinguishable pathological phenotype from the sporadic form of disease, suggested LRRK2 as the culprit to provide understanding for both familial and sporadic PD cases. LRRK2 is a large protein with both GTPase and kinase functions. Mutations segregating with PD reside within the enzymatic core of LRRK2, suggesting the modification of its activity greatly impacts disease onset and progression. Although progress has been gained since its discovery in 2004, there is still much to be understood regarding LRRK2's physiological and neurotoxic properties. Unsurprisingly, given the presence of multiple enzymatic domains, LRRK2 has been associated with a diverse set of cellular functions and signalling pathways including mitochondrial function, vesicle trafficking together with endocytosis, retromer complex modulation and autophagy. This review will discuss the state of current knowledge for the role of LRRK2 in health and disease with discussion of potential substrates of phosphorylation and functional partners with particular emphasis on signalling mechanisms. As well, the use of immune cells in LRRK2 research and the role of oxidative stress as a regulator of LRRK2 activity and cellular function shall also be discussed. This article is protected by copyright. All rights reserved

Computational analysis of the LRRK2 interactome.

LRRK2 was identified in 2004 as the causative protein product of the Parkinson's disease locus designated PARK8. In the decade since then, genetic studies have revealed at least 6 dominant mutations in LRRK2 linked to Parkinson's disease, alongside one associated with cancer. It is now well established that coding changes in LRRK2 are one of the most common causes of Parkinson's. Genome-wide association studies (GWAs) have, more recently, reported single nucleotide polymorphisms (SNPs) around the LRRK2 locus to be associated with risk of developing sporadic Parkinson's disease and inflammatory bowel disorder. The functional research that has followed these genetic breakthroughs has generated an extensive literature regarding LRRK2 pathophysiology; however, there is still no consensus as to the biological function of LRRK2. To provide insight into the aspects of cell biology that are consistently related to LRRK2 activity, we analysed the plethora of candidate LRRK2 interactors available through the BioGRID and IntAct data repositories. We then performed GO terms enrichment for the LRRK2 interactome. We found that, in two different enrichment portals, the LRRK2 interactome was associated with terms referring to transport, cellular organization, vesicles and the cytoskeleton. We also verified that 21 of the LRRK2 interactors are genetically linked to risk for Parkinson's disease or inflammatory bowel disorder. The implications of these findings are discussed, with particular regard to potential novel areas of investigation

Dysfunction of the autophagy/lysosomal degradation pathway is a shared feature of the genetic synucleinopathies.

The past decade has witnessed huge advances in our understanding of the genetics underlying Parkinson's disease. Identifying commonalities in the biological function of genes linked to Parkinson's provides an opportunity to elucidate pathways that lead to neuronal degeneration and eventually to disease. We propose that the genetic forms of Parkinson's disease largely associated with α-synuclein-positive neuropathology (SNCA, LRRK2, and GBA) are brought together by involvement in the autophagy/lysosomal pathway and that this represents a unifying pathway to disease in these cases

Wide-range optical spin orientation in Ge from near-infrared to visible light

Ge-based spin-photodiodes have been employed to investigate the spectral dependence of optical spin orientation in germanium, in the range 400-1550 nm. We found the expected maximum in the spin polarization of photocarriers for excitation at the direct gap in Γ (1550 nm) and a second sizable peak due to photogeneration in the L valleys (530 nm). Data suggest distinct spin depolarization mechanisms for excitation at Γ and L, with shorter spin relaxation times whether the X point is involved. These devices can be used as integrated photon-helicity detectors over a wide spectral range

Solid-phase synthesis of peptides containing reverse-turn mimetic bicyclic lactams

The solid-phase synthesis and characterization of a series of peptides (4-15) containing reverse-turn mimetic bicyclic lactams is reported. The bicyclic lactams (1a, 1b) possess high structural similarity to the two central residues of a Pturn. Amino acid conjugates of these bicyclic lactams were synthesized on solid supports following a g-fluorenylmethoxycarbonyl (FMOC) protection strategy on WangMerrifield resin. Coupling between amino acids was accomplished by means of diisopropylcarbodiimide (DIC)/ hydroxyazabenzotriazole (HOAt). Coupling between amino acids and the mimics was performed with the potent Carpino's reagent O-(7-azabenzotriazol-1-yl)-N,N,N',N'-tetramelhyluronium hexafluorophosphate (HATU). The final compounds were cleaved from the resin and obtained as N-acetylated methyl esters or benzyl amides

Plasmonic gold helices for the visible range fabricated by oxygen plasma purification of electron beam induced deposits

Electron beam induced deposition (EBID) currently provides the only direct writing technique for truly three-dimensional nanostructures with geometrical features below 50 nm. Unfortunately, the depositions from metal-organic precursors suffer from a substantial carbon content. This hinders many applications, especially in plasmonics where the metallic nature of the geometric surfaces is mandatory. To overcome this problem a post-deposition treatment with oxygen plasma at room temperature was investigated for the purification of gold containing EBID structures. Upon plasma treatment, the structures experience a shrinkage in diameter of about 18 nm but entirely keep their initial shape. The proposed purification step results in a core-shell structure with the core consisting of mainly unaffected EBID material and a gold shell of about 20 nm in thickness. These purified structures are plasmonically active in the visible wavelength range as shown by dark field optical microscopy on helical nanostructures. Most notably, electromagnetic modeling of the corresponding scattering spectra verified that the thickness and quality of the resulting gold shell ensures an optical response equal to that of pure gold nanostructures

The effect of diameter variability and medullation of wool on Fibre Fineness Distribution Analyser (FFDA) measurements.

No presente trabalho foram investigados os efeitos da medulação e da variabilidade de diâmetro da lã sobre as medidas de diâmetro no FFDA. Foram desenvolvidas equações para corrigir os resultados oriundos do FFDA, de acordo com o grau de medulação das amostras. Os resultados do trabalho indicaram que na calibração do FFDA deveria ser incluído um "top" de lã com maior diâmetro médio do que os usados correntemente. Isto melhoraria os resultados para as lãs mais grossas.The effect of medullation and variability of fibre diameter on FFDA measurements were investigated. For a FFDA fitted with the expanding (new) cell, medullated wools and more variable wools gave finer results than those obtained with the projection microscope. Equations correcting FFDA results for the degree of medullation are presented. It is suggested that calibration using a coarser top than those currently in use would improve measurements on coarse wool