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Vacuolar Protein Sorting Genes in Parkinson's Disease: A Re-appraisal of Mutations Detection Rate and Neurobiology of Disease

View Article: PubMed Central - PubMed

ABSTRACT

Mammalian retromers play a critical role in protein trans-membrane sorting from endosome to the trans-Golgi network (TGN). Recently, retromer alterations have been related to the onset of Parkinson's Disease (PD) since the variant p.Asp620Asn in VPS35 (Vacuolar Protein Sorting 35) was identified as a cause of late onset PD. This variant causes a primary defect in endosomal trafficking and retromers formation. Other mutations in VPS genes have been reported in both sporadic and familial PD. These mutations are less defined. Understanding the specific prevalence of all VPS gene mutations is key to understand the relevance of retromers impairment in the onset of PD. A number of PD-related mutations despite affecting different biochemical systems (autophagy, mitophagy, proteasome, endosomes, protein folding), all converge in producing an impairment in cell clearance. This may explain how genetic predispositions to PD may derive from slightly deleterious VPS mutations when combined with environmental agents overwhelming the clearance of the cell. This manuscript reviews genetic data produced in the last 5 years to re-define the actual prevalence of VPS gene mutations in the onset of PD. The prevalence of p.Asp620Asn mutation in VPS35 is 0.286 of familial PD. This increases up to 0.548 when considering mutations affecting all VPS genes. This configures mutations in VPS genes as the second most frequent autosomal dominant PD genotype. This high prevalence, joined with increased awareness of the role played by retromers in the neurobiology of PD, suggests environmentally-induced VPS alterations as crucial in the genesis of PD.

No MeSH data available.


Related in: MedlinePlus

VPS mutations and retromer dysfunction. This cartoon reports the most relevant effects of VPS dysfunction on the molecular mechanisms involved in cellular trafficking. Mutations (nr.1) occurring in any of the Vacuolar Protein Sorting components of the retromer (VPS35, VPS26, and VPS29) may lead to increased levels of misfolded proteins, thereby causing abnormal sorting and trafficking. In an attempt to get rid of misfolded proteins, the routine trafficking may shift from endosomes and trans-Golgi network (TGN) to the cell membrane to produce the release of aberrant cargoes. Diffusible retromers may be key in neurodegenerative disorders, posing this unconventional mechanism of cell-to-cell communication as a cause of disease spreading. Retromer dysfunction may also derive from mutations (nr.2) impairing the retrograde transport of cation-independent mannose-6-phosphate receptor (CIM6PR), which in turn becomes unable to bind cathepsin D and other proteases to the TGN, to be delivered to the endosome (Miura et al., 2014). Since cathepsin D is an endosome–lysosome protease which is crucial for degrading α-synuclein, this may explain the occurrence of α-synuclein accumulation also in the course of retromer-related PD. The relevance of the endosomal/retromer/exosome compartment in PD is supported by the interaction of VPS35 with parkin by promoting Rab7 ubiquitination. In fact, Parkin mutations (nr.3) are associated with retromer dysfunctions (Song et al., 2016). In line with consistent finding on mitochondrial alterations in PD, VPS35 was shown to modulate mitochondrial integrity and mitochondrial turnover (Tang et al., 2015b; Wang et al., 2016).
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Figure 1: VPS mutations and retromer dysfunction. This cartoon reports the most relevant effects of VPS dysfunction on the molecular mechanisms involved in cellular trafficking. Mutations (nr.1) occurring in any of the Vacuolar Protein Sorting components of the retromer (VPS35, VPS26, and VPS29) may lead to increased levels of misfolded proteins, thereby causing abnormal sorting and trafficking. In an attempt to get rid of misfolded proteins, the routine trafficking may shift from endosomes and trans-Golgi network (TGN) to the cell membrane to produce the release of aberrant cargoes. Diffusible retromers may be key in neurodegenerative disorders, posing this unconventional mechanism of cell-to-cell communication as a cause of disease spreading. Retromer dysfunction may also derive from mutations (nr.2) impairing the retrograde transport of cation-independent mannose-6-phosphate receptor (CIM6PR), which in turn becomes unable to bind cathepsin D and other proteases to the TGN, to be delivered to the endosome (Miura et al., 2014). Since cathepsin D is an endosome–lysosome protease which is crucial for degrading α-synuclein, this may explain the occurrence of α-synuclein accumulation also in the course of retromer-related PD. The relevance of the endosomal/retromer/exosome compartment in PD is supported by the interaction of VPS35 with parkin by promoting Rab7 ubiquitination. In fact, Parkin mutations (nr.3) are associated with retromer dysfunctions (Song et al., 2016). In line with consistent finding on mitochondrial alterations in PD, VPS35 was shown to modulate mitochondrial integrity and mitochondrial turnover (Tang et al., 2015b; Wang et al., 2016).

Mentions: The re-appraisal of the prevalence of VPS genetic alterations, apart from re-defining the relevance of this class of mutations in causing F-PD, is helpful to analyze the potential dysfunctions of VPS in producing sporadic PD. In fact, the process of disclosing genetic determinants of PD provides molecular markers which often are shared by all (genetic and sporadic) PD cases. The proof of principle is represented by the case of alpha synuclein, which is responsible for rare F-PD but it is found to be altered at molecular level in almost all PD phenotypes where it represents the hallmark of proteinaceous aggregates known as Lewy Bodies (Spillantini et al., 1997). In fact, alpha synuclein provided the basis to unravel the general mechanisms of action of misfolded proteins, which is relevant to interpret the disease course both in familial and sporadic PD (Fornai et al., 2005a,b,c, 2006, 2008; Giorgi et al., 2006; Iacovelli et al., 2006; Mauceli et al., 2006; Lazzeri et al., 2007; Ferrucci et al., 2008). In keeping with this, the role of VPS is key in releasing protein-enriched exosomes. This is critical to understand disease propagation through synaptically connected regions along the whole CNS. In this way, VPS mutations may be a pivot to understand cell-to-cell transmission of protein cargoes through exosomes (Danzer et al., 2012; Poehler et al., 2014; Tsunemi et al., 2014; Emmanouilidou and Vekrellis, 2016; Lööv et al., 2016; Figure 1). Thus, an in depth analysis of VPS alterations is expected to disclose the anatomical basis of disease progression as recently described (Hawkes et al., 2010; Del Tredici and Braak, 2013; Holmqvist et al., 2014; Garcia-Esparcia et al., 2015; Lamberts et al., 2015). Within this scenario one should consider that VPS is involved in clearing misfolded proteins as well as a variety of cell material within exosomes and diffusible retromers (Figure 1). A knowledge of cell pathology produced by specific variants of VPS is relevant to describe the molecular mechanisms involved in abnormal cell-to-cell transmission. In keeping with this, it should be considered that VPS35 mutations represent an autosomal dominant genetic disorder. This suggests a pathological gain of function. Thus, one may hypothesize that an overactive exosome may increase retromers availability, thus contributing to the spreading of pathological cargoes along the CNS. If this hypothesis is correct one should expect that decreased retromer activity may exert a protective role. Unexpectedly, this is just the opposite of what has been recently indicated by Tang et al. (2015b), who demonstrated that, the loss of retromer activity leads to the loss of dopamine-containing neurons. Thus, it is likely that mutations leading to PD impair retromer activity, rather than providing an enhancement of retromer function. The dominant nature of these mutations imply that the activity of retromers needs to be highly preserved in order to keep cell homeostasis. Since the main function of retromers consists in transporting cell material from the plasma membrane to the trans Golgi network and back again, it is likely that even a slight disruption of this trafficking may impair cell survival. In fact, when assayed in the presence of an excess of alpha synuclein, in alpha synuclein transgenic mice, the concomitant over-expression of native VPS35 counteracts alpha-synuclein-dependent toxicity (Dhungel et al., 2015). In order to produce its beneficial effects VPS35 needs to be structurally intact since the up-regulation of mutant VPS35 worsens the neurotoxic effects produced by alpha synuclein (Dhungel et al., 2015). In light of these findings the effective activity of VPS appears to be critical to promote retromer function, thus providing a key step in the removal of toxic substrates (Wang et al., 2016; Figure 1). This is confirmed by Sowada et al. (2016) who showed protection from copper toxicity in yeast over-expressing VPS35, while copper and alpha-synuclein toxicity is enhanced in the same cells upon VPS35 dysfunction produced by VPS35 mutations. The natural function of VPS35 is bound to the PARK2 gene described as parkin (Kitada et al., 1998). In fact, despite multiple roles exerted by parkin as a E3 ubiquitin ligase (modulating both proteasome and autophagy activity), it seems that the most relevant effects are produced by its interaction with the endosomal compartment. Parkin was recently shown to regulate endosomal activity just based on its interaction with VPS35 (Song et al., 2016). These data strongly suggest that endocytic compartment is likely to be highly relevant in PD. This concept does not rule out previous findings showing both proteasome and autophagosome dysfunction. In fact all these compartments eventually merge to produce an ultimate organelle which fuses with lysosomes (Lenzi et al., 2016). The specific fate of endosomes is related to the chance that, despite routinely shuttling toward the trans Golgi network, this compartment may be delivered to the cell membrane to be released. This is effectively commented by Zhang and Schekman (2013) under the title “unconventional secretions, unconventional solutions.” Thus, we may consider that a dysfunction in the VPS complex shifts the routine trafficking from endosomes and trans Golgi network to the cell membrane to produce the release of toxic cargoes (Figure 1). In keeping with this hypothesis we may argue that a mutation in the VPS complex produces an abnormal cargoes release since the natural intracellular trafficking is no longer able to clean the cells from overwhelming retromers. This may explain why Song et al. (2016) described the occurrence of abnormal endosomes within parkin deficient cells where the endosomal cargoes were delivered to the extracellular space to be released. The emphasis which derives from recent findings on the pivotal role of the endosomal/retromer/exosome compartment in PD pathogenesis remains to be clearly balanced. For instance, recent studies demonstrate that a mutation of VPS35 alters the mitochondrial turnover (Tang et al., 2015a,b; Wang et al., 2016). These findings pose uncertain outcomes, which remain difficult to explain simply based on the current knowledge on the endosomal compartment. Understanding the significance of various mutations of VPS is key to dissect the site-specific relevance of each specific VPS isoform and it may help to understand why certain VPS mutations are associated with PD while others are linked to AD or may produce mixed disease phenotypes known as atypical PD.


Vacuolar Protein Sorting Genes in Parkinson's Disease: A Re-appraisal of Mutations Detection Rate and Neurobiology of Disease
VPS mutations and retromer dysfunction. This cartoon reports the most relevant effects of VPS dysfunction on the molecular mechanisms involved in cellular trafficking. Mutations (nr.1) occurring in any of the Vacuolar Protein Sorting components of the retromer (VPS35, VPS26, and VPS29) may lead to increased levels of misfolded proteins, thereby causing abnormal sorting and trafficking. In an attempt to get rid of misfolded proteins, the routine trafficking may shift from endosomes and trans-Golgi network (TGN) to the cell membrane to produce the release of aberrant cargoes. Diffusible retromers may be key in neurodegenerative disorders, posing this unconventional mechanism of cell-to-cell communication as a cause of disease spreading. Retromer dysfunction may also derive from mutations (nr.2) impairing the retrograde transport of cation-independent mannose-6-phosphate receptor (CIM6PR), which in turn becomes unable to bind cathepsin D and other proteases to the TGN, to be delivered to the endosome (Miura et al., 2014). Since cathepsin D is an endosome–lysosome protease which is crucial for degrading α-synuclein, this may explain the occurrence of α-synuclein accumulation also in the course of retromer-related PD. The relevance of the endosomal/retromer/exosome compartment in PD is supported by the interaction of VPS35 with parkin by promoting Rab7 ubiquitination. In fact, Parkin mutations (nr.3) are associated with retromer dysfunctions (Song et al., 2016). In line with consistent finding on mitochondrial alterations in PD, VPS35 was shown to modulate mitochondrial integrity and mitochondrial turnover (Tang et al., 2015b; Wang et al., 2016).
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Related In: Results  -  Collection

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Figure 1: VPS mutations and retromer dysfunction. This cartoon reports the most relevant effects of VPS dysfunction on the molecular mechanisms involved in cellular trafficking. Mutations (nr.1) occurring in any of the Vacuolar Protein Sorting components of the retromer (VPS35, VPS26, and VPS29) may lead to increased levels of misfolded proteins, thereby causing abnormal sorting and trafficking. In an attempt to get rid of misfolded proteins, the routine trafficking may shift from endosomes and trans-Golgi network (TGN) to the cell membrane to produce the release of aberrant cargoes. Diffusible retromers may be key in neurodegenerative disorders, posing this unconventional mechanism of cell-to-cell communication as a cause of disease spreading. Retromer dysfunction may also derive from mutations (nr.2) impairing the retrograde transport of cation-independent mannose-6-phosphate receptor (CIM6PR), which in turn becomes unable to bind cathepsin D and other proteases to the TGN, to be delivered to the endosome (Miura et al., 2014). Since cathepsin D is an endosome–lysosome protease which is crucial for degrading α-synuclein, this may explain the occurrence of α-synuclein accumulation also in the course of retromer-related PD. The relevance of the endosomal/retromer/exosome compartment in PD is supported by the interaction of VPS35 with parkin by promoting Rab7 ubiquitination. In fact, Parkin mutations (nr.3) are associated with retromer dysfunctions (Song et al., 2016). In line with consistent finding on mitochondrial alterations in PD, VPS35 was shown to modulate mitochondrial integrity and mitochondrial turnover (Tang et al., 2015b; Wang et al., 2016).
Mentions: The re-appraisal of the prevalence of VPS genetic alterations, apart from re-defining the relevance of this class of mutations in causing F-PD, is helpful to analyze the potential dysfunctions of VPS in producing sporadic PD. In fact, the process of disclosing genetic determinants of PD provides molecular markers which often are shared by all (genetic and sporadic) PD cases. The proof of principle is represented by the case of alpha synuclein, which is responsible for rare F-PD but it is found to be altered at molecular level in almost all PD phenotypes where it represents the hallmark of proteinaceous aggregates known as Lewy Bodies (Spillantini et al., 1997). In fact, alpha synuclein provided the basis to unravel the general mechanisms of action of misfolded proteins, which is relevant to interpret the disease course both in familial and sporadic PD (Fornai et al., 2005a,b,c, 2006, 2008; Giorgi et al., 2006; Iacovelli et al., 2006; Mauceli et al., 2006; Lazzeri et al., 2007; Ferrucci et al., 2008). In keeping with this, the role of VPS is key in releasing protein-enriched exosomes. This is critical to understand disease propagation through synaptically connected regions along the whole CNS. In this way, VPS mutations may be a pivot to understand cell-to-cell transmission of protein cargoes through exosomes (Danzer et al., 2012; Poehler et al., 2014; Tsunemi et al., 2014; Emmanouilidou and Vekrellis, 2016; Lööv et al., 2016; Figure 1). Thus, an in depth analysis of VPS alterations is expected to disclose the anatomical basis of disease progression as recently described (Hawkes et al., 2010; Del Tredici and Braak, 2013; Holmqvist et al., 2014; Garcia-Esparcia et al., 2015; Lamberts et al., 2015). Within this scenario one should consider that VPS is involved in clearing misfolded proteins as well as a variety of cell material within exosomes and diffusible retromers (Figure 1). A knowledge of cell pathology produced by specific variants of VPS is relevant to describe the molecular mechanisms involved in abnormal cell-to-cell transmission. In keeping with this, it should be considered that VPS35 mutations represent an autosomal dominant genetic disorder. This suggests a pathological gain of function. Thus, one may hypothesize that an overactive exosome may increase retromers availability, thus contributing to the spreading of pathological cargoes along the CNS. If this hypothesis is correct one should expect that decreased retromer activity may exert a protective role. Unexpectedly, this is just the opposite of what has been recently indicated by Tang et al. (2015b), who demonstrated that, the loss of retromer activity leads to the loss of dopamine-containing neurons. Thus, it is likely that mutations leading to PD impair retromer activity, rather than providing an enhancement of retromer function. The dominant nature of these mutations imply that the activity of retromers needs to be highly preserved in order to keep cell homeostasis. Since the main function of retromers consists in transporting cell material from the plasma membrane to the trans Golgi network and back again, it is likely that even a slight disruption of this trafficking may impair cell survival. In fact, when assayed in the presence of an excess of alpha synuclein, in alpha synuclein transgenic mice, the concomitant over-expression of native VPS35 counteracts alpha-synuclein-dependent toxicity (Dhungel et al., 2015). In order to produce its beneficial effects VPS35 needs to be structurally intact since the up-regulation of mutant VPS35 worsens the neurotoxic effects produced by alpha synuclein (Dhungel et al., 2015). In light of these findings the effective activity of VPS appears to be critical to promote retromer function, thus providing a key step in the removal of toxic substrates (Wang et al., 2016; Figure 1). This is confirmed by Sowada et al. (2016) who showed protection from copper toxicity in yeast over-expressing VPS35, while copper and alpha-synuclein toxicity is enhanced in the same cells upon VPS35 dysfunction produced by VPS35 mutations. The natural function of VPS35 is bound to the PARK2 gene described as parkin (Kitada et al., 1998). In fact, despite multiple roles exerted by parkin as a E3 ubiquitin ligase (modulating both proteasome and autophagy activity), it seems that the most relevant effects are produced by its interaction with the endosomal compartment. Parkin was recently shown to regulate endosomal activity just based on its interaction with VPS35 (Song et al., 2016). These data strongly suggest that endocytic compartment is likely to be highly relevant in PD. This concept does not rule out previous findings showing both proteasome and autophagosome dysfunction. In fact all these compartments eventually merge to produce an ultimate organelle which fuses with lysosomes (Lenzi et al., 2016). The specific fate of endosomes is related to the chance that, despite routinely shuttling toward the trans Golgi network, this compartment may be delivered to the cell membrane to be released. This is effectively commented by Zhang and Schekman (2013) under the title “unconventional secretions, unconventional solutions.” Thus, we may consider that a dysfunction in the VPS complex shifts the routine trafficking from endosomes and trans Golgi network to the cell membrane to produce the release of toxic cargoes (Figure 1). In keeping with this hypothesis we may argue that a mutation in the VPS complex produces an abnormal cargoes release since the natural intracellular trafficking is no longer able to clean the cells from overwhelming retromers. This may explain why Song et al. (2016) described the occurrence of abnormal endosomes within parkin deficient cells where the endosomal cargoes were delivered to the extracellular space to be released. The emphasis which derives from recent findings on the pivotal role of the endosomal/retromer/exosome compartment in PD pathogenesis remains to be clearly balanced. For instance, recent studies demonstrate that a mutation of VPS35 alters the mitochondrial turnover (Tang et al., 2015a,b; Wang et al., 2016). These findings pose uncertain outcomes, which remain difficult to explain simply based on the current knowledge on the endosomal compartment. Understanding the significance of various mutations of VPS is key to dissect the site-specific relevance of each specific VPS isoform and it may help to understand why certain VPS mutations are associated with PD while others are linked to AD or may produce mixed disease phenotypes known as atypical PD.

View Article: PubMed Central - PubMed

ABSTRACT

Mammalian retromers play a critical role in protein trans-membrane sorting from endosome to the trans-Golgi network (TGN). Recently, retromer alterations have been related to the onset of Parkinson's Disease (PD) since the variant p.Asp620Asn in VPS35 (Vacuolar Protein Sorting 35) was identified as a cause of late onset PD. This variant causes a primary defect in endosomal trafficking and retromers formation. Other mutations in VPS genes have been reported in both sporadic and familial PD. These mutations are less defined. Understanding the specific prevalence of all VPS gene mutations is key to understand the relevance of retromers impairment in the onset of PD. A number of PD-related mutations despite affecting different biochemical systems (autophagy, mitophagy, proteasome, endosomes, protein folding), all converge in producing an impairment in cell clearance. This may explain how genetic predispositions to PD may derive from slightly deleterious VPS mutations when combined with environmental agents overwhelming the clearance of the cell. This manuscript reviews genetic data produced in the last 5 years to re-define the actual prevalence of VPS gene mutations in the onset of PD. The prevalence of p.Asp620Asn mutation in VPS35 is 0.286 of familial PD. This increases up to 0.548 when considering mutations affecting all VPS genes. This configures mutations in VPS genes as the second most frequent autosomal dominant PD genotype. This high prevalence, joined with increased awareness of the role played by retromers in the neurobiology of PD, suggests environmentally-induced VPS alterations as crucial in the genesis of PD.

No MeSH data available.


Related in: MedlinePlus