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 aggregation, whereas other three are shown to delay the aggregation kinetics. The membrane binding studies also suggest that few of these PD mutants strongly bind to synthetic membrane vesicles, while others are shown to have attenuated membrane binding ability. Furthermore, the PD mutations do not drastically alter the toxicity of α-Syn oligomers/fibrils. Although according to recent suggestions that early formed oligomers are the most potent toxic species responsible for PD, only p.A30P mutant is shown to form faster oligomers and delayed conversion from oligomers to fibrils. Therefore, it is difficult to establish a unifying mechanism of how familial PD associated mutations affect the α-Syn structure, aggregation and function for their disease association. It is possible that each PD associated mutation alters α-Syn biology in a unique way, which might be responsible for disease pathogenesis. In this review, we discuss the structure function of α- Syn and how these are altered due to the PD associated mutations and their relationship to disease pathogenesis.

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. These findings have spurred great interest in drug development approaches, and various specific LRRK2 kinase inhibitors have been developed. However, LRRK2 is a largely ubiquitously expressed protein, and inhibiting its function in some non-neuronal tissues has raised safety liability issues for kinase inhibitor approaches. Therefore, understanding the cellular and cell type-specific role(s) of LRRK2 has become of paramount importance. This review will highlight current knowledge on the precise biochemical activities of normal and pathogenic LRRK2, and highlight the most common proposed cellular roles so as to gain a better understanding of the cell type-specific effects of LRRK2 modulators.

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 trafficking pathways, including recycling to the plasma membrane and regulation of cell polarity. In recent years, genetic, cellular, pharmacological and animal model studies have identified retromer and its interacting proteins as being linked to familial forms of neurodegenerative diseases such as Alzheimer’s (AD) and Parkinson’s (PD). Here, this commentary will summarize recently identified point mutations in retromer linked to PD, and explore the molecular functions of retromer that may be relevant to disease progression.

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 experimental findings can help decide whether individual variants are pathogenic or not.

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 in our understanding of Fbxo7 function in Parkinson’s disease, with respect to these mutations and where they occur in the Fbxo7 protein. We hypothesize that many of Fbxo7 functions contribute to its role in PD pathogenesis.

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 domains similar to other P-type ATPases which mainly transport cations. Consistently, recent studies suggest that human ATP13A2 may preferably regulate Zn2+, while ATP13A2 from other species have different substrate selectivity. Until now, fourteen mutations in ATP13A2 have been associated with KRS, while other mutations have been reported in association with neuronal ceroid lipofuscinosis (NCL) and early-onset PD. Experimentally, these disease- associated ATP13A2 mutations have been shown to confer loss-of-function to the protein by disrupting its protein structure and function to varying degrees, ranging from impairment in ATPase function to total loss of protein, confirming their pathogenicity. Loss of functional ATP13A2 has been shown to induce Zn2+ dyshomeostasis. Disturbances in Zn2+ homeostasis impair mitochondrial and lysosomal function which leads to loss of mitochondrial bioenergetic capacity and accumulation of lysosomal substrates such as α-synuclein and lipofuscin. Additionally, ATP13A2 appears to be involved in α-synuclein externalisation through its Zn2+-regulating activity. In this review, we will discuss all the reported KRS/NCL-associated ATP13A2 mutations along with several PD-associated mutations which have been experimentally assessed, in respect to their impact on the protein structure and function of ATP13A2.

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 or misfolding that results in neurotoxicity. A better understanding of the molecular mechanism and composition of these cellular inclusions will help shed light on the progression of misfolding-associated neurodegenerative disorders. Ubiquitin carboxyl-terminal hydrolase L1 (UCH-L1) is found to co-aggregate with α-synuclein (αS), the major component of LBs. Several familial mutations of UCH-L1, namely p.Ile93Met (p.I93M), p.Glu7Ala (p.E7A), and p.Ser18Tyr (p.S18Y), are associated with PD and other neurodegenerative disorders. Here, we review recent progress and recapitulate the impact of PD-associated mutations of UCH-L1 in the context of their biological functions gleaned from biochemical and biophysical studies. Finally, we summarize the effect of these genetic mutations and post-translational modifications on the association of UCHL1 and PD in terms of loss of cellular functions or gain of cellular toxicity.

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 ER stress-mediated apoptosis. Recently, the HtrA2 protein has received great attention for its potential role in neurodegeneration. Here, we review the current knowledge and pathophysiological functions of the HtrA2 protein in neurodegenerative disorders such as Parkinson’s and Alzheimer's disease.

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 shown that there are significantly more cases bearing GBA mutations than those found among healthy individuals. Functional studies have proven an interaction between α-synuclein and GBA, the levels of which presented an inverse correlation. Mutant GBA proteins cause increases in α-synuclein levels, while an inhibition of GBA by α-synuclein has been also demonstrated. Saposin C, a coactivator of GBA, has been shown to protect GBA from this inhibition. Among the GBA variants associated with Parkinson disease, E326K seems to be one of the most prevalent. Interestingly, it is involved in Gaucher disease only when it forms part of a double-mutant allele, usually with the L444P mutation. Structural analyses have revealed that both residues (E326 and L444) interact with Saposin C and, probably, also with α-synuclein. This could explain the antagonistic role of these two proteins in relation to GBA.

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 compile the knowledge about other proteins with a more general role in neurodegenerative diseases (MAPT) or for which less data is available due to its recent discovery (EIF4G1, DNAJC13), the lack of structural or functional data (as for PLA2G6 or DNAJC6), or even their doubtful association with the disease (as for GIGYF2, SYNJ1 and SPR). Also the cellular pathways involved in this disease are reviewed, with the goal of having an overview of the effects on the proteins and its possible role in the disease. This knowledge could also serve as the basis for designing tools that may potentially be used as a treatment for the disease, such as inhibitory or activating molecules, as well as other involved in regulating the half-life of the proteins involved.