Current Protein and Peptide Science - Volume 18, Issue 7, 2017

α-Synuclein (α-Syn) aggregation is directly associated with Parkinson’s disease (PD) pathogenesis. In vitro aggregation and in vivo animal model studies of α-Syn recapitulate many features of the disease pathogenesis. Six familial PD associated mutations of α-Syn have been discovered; many of which are associated with early onset PD. Three of PD associated mutations have been shown to accelerate the α-Syn aggrega Read More

Mutations in LRRK2 comprise the most common cause for familial Parkinson’s disease (PD), and variations increase risk for sporadic disease, implicating LRRK2 in the entire disease spectrum. LRRK2 is a large protein harbouring both GTPase and kinase domains which display measurable catalytic activity. Most pathogenic mutations increase the kinase activity, with increased activity being cytotoxic under certain conditions Read More

The retromer complex is a highly conserved membrane trafficking assembly composed of three proteins - Vps26, Vps29 and Vps35 - that were identified over a decade ago in Saccharomyces cerevisiae (S. cerevisiae). Initially, mammalian retromer was shown to sort transmembrane proteins from the endosome to the trans-Golgi network (TGN), though recent work has identified a critical role for retromer in multiple t Read More

Early onset Parkinson’s disease can be caused by variants in the PINK1, Parkin, and DJ-1 genes. Since their initial discoveries, hundreds of variants have been found in these genes that are associated with a Parkinsonian phenotype. This review will briefly discuss the functions of the protein products of the three genes, then focus on the effects that disease associated variants have on these functions. We will also discuss how Read More

Fbxo7/PARK15 has well-defined roles, acting as part of a Skp1-Cul1-F box protein (SCF)- type E3 ubiquitin ligase and also having SCF-independent activities. Mutations within FBXO7 have been found to cause an early-onset Parkinson's disease, and these are found within or near to its functional domains, including its F-box domain (FBD), its proline rich region (PRR), and its ubiquitinlike domain (Ubl). We highlight recent advances i Read More

Kufor-Rakeb syndrome (KRS) is an autosomal recessive form of Parkinson’s disease (PD) with juvenile onset of parkinsonism, often accompanied by extra clinical features such as supranuclear gaze palsy, dementia and generalised brain atrophy. Mutations in ATP13A2, associated with the PARK9 locus (chromosome 1p36) have been identified in KRS patients. ATP13A2 encodes a lysosomal P5B-type ATPase which has functional do Read More

Parkinson’s disease (PD) is one of the most common progressive neurodegenerative disorders in modern society. The disease involves many genetic risk factors as well as a sporadic pathogenesis that is age- and environment-dependent. Of particular interest is the formation of intra-neural fibrillar aggregates, namely Lewy bodies (LBs), the histological hallmark of PD, which results from aberrant protein homeostasis o Read More

High-temperature-requirement A2 (HtrA2)/Omi/PARK13 is a serine protease with extensive homology to the Escherichia coli HtrAs that are required for bacterial survival at high temperatures. The HtrA2 protein is a key modulator of mitochondrial molecular quality control but under stressful conditions it is released into the cytosol, where it promotes cell death by various pathways, including caspase-dependent pathway and E Read More

Gaucher disease is an autosomal recessive lysosomal storage disorder, caused by mutations in the GBA gene. The frequency of Gaucher disease patients and heterozygote carriers that developed Parkinson disease has been found to be above that of the control population. This fact suggests that mutations in the GBA gene can be involved in Parkison’s etiology. Analysis of large cohorts of patients with Parkinson disease has sh Read More

In order to explain the molecular causes of Parkinson’s Disease (PD) it is important to understand the effect that mutations described as causative of the disease have at the functional level. In this special issue, several authors have been reviewing the effects in PD and other parkinsonisms of mutations described in LRRK2, α-synuclein, PINK1-Parkin-DJ-1, UCHL1, ATP13A2, GBA, VPS35, FBOX7 and HTRA2. In this review, we com Read More