In vivo evidence of pathogenicity of VPS35 mutations in the Drosophila

Wang, Hua-shan; Toh, Joanne; Ho, Patrick; Tio, Murni; Zhao, Yongxiang; Tan, Eng‐King

doi:10.1186/s13041-014-0073-y

Cited by 40 publications

(26 citation statements)

References 24 publications

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“…If viable, this therapeutic approach would not only turn out to be beneficial for AD, but perhaps also be useful for other disorders where endosomal dysfunction has been described, for example PD [23]. Several studies have recently implicated the retromer complex itself in PD [24][25][26]. To date, a dozen genes have been implicated in PD, including a point mutation (D620N) in Vps35, which results in autosomal dominant familial PD [27,28].…”

Section: Retromer In Other Diseasesmentioning

confidence: 99%

The Use of Pharmacological Retromer Chaperones in Alzheimer's Disease and other Endosomal-related Disorders

et al. 2015

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The retromer is an evolutionary conserved multiprotein complex involved in the sorting and retrograde trafficking of cargo from endosomal compartments to the Golgi network and to the cell surface. The neuronal retromer traffics the amyloid precursor protein away from the endosomes, a site where amyloid precursor protein is enzymatically cleaved into pathogenic fragments in Alzheimer's disease. In recent years, deficiencies in retromer-mediated transport have been implicated in several neurological and non-neurological diseases, including Parkinson's disease, suggesting that improving the efficacy of the retromer trafficking pathway would result in decreased pathology. We recently identified a new family of small molecules that appear to stabilize the interaction between members of the retromer complex and enhance its function in neurons: the retromer pharmacological chaperones. Here we discuss the role of these molecules in the improvement of retromer trafficking and endosomal dysfunction, as well as their potential as therapeutics for neurological and non-neurological disorders.

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Section: Retromer In Other Diseasesmentioning

confidence: 99%

The Use of Pharmacological Retromer Chaperones in Alzheimer's Disease and other Endosomal-related Disorders

et al. 2015

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“…Interestingly, these findings suggest greater susceptibility to cellular stress and a heightened level of apoptosis in the presence of D620N-containing retromer, consistent with recent work published using Drosophila [261] . Whether these results are a secondary consequence of receptor mis-trafficking or impact on other pathways directly is not known.…”

Section: Retromer and Parkinson's Diseasesupporting

confidence: 80%

“…This is further supported by Bi and colleagues where expression of wild-type Vps35 but not the pathogenic D620N mutation in primary rat neurons isolated from the midbrain significantly increased cell viability following exposure to mitochondrial toxin MPP+ [336]. Whether the loss of neuronal viability witnessed with the D620N mutation is also observed in other Vps35 mutations, such as R524W, is currently unknown, however recent work by Wang et al, 2014 suggests that expression of Vps35 P316S modestly impacts DA neuron viability in Drosophila [261]. the trafficking of a mitochondrial protein ligase [337].…”

Section: Retromer Mediated Neuroprotectionsupporting

confidence: 61%

“…While such cell lines provide excellent models for further study, genetically modifying either rat or mouse genomes to express Vps35 variants, such as D620N, will be more relevant models to assess the impact of the Vps35 variants on cellular trafficking and neurodegeneration. They will open new avenues to examine Vps35-linked pathogenesis in the context of a whole organism -similarly to a recent publication using Drosophila, which reported reduced life-span of the flies expressing human Vps35 D620N [261].…”

Section: Future Perspectivesmentioning

confidence: 94%

“…However, recent in vivo data of Drosophila expressing human Vps35 D620N mutations revealed the loss of Tyrosine Hydroxylase (TH)-positive Dopaminergic neurons, decreased lifespan and heightened sensitivity to the mitochondrial toxin, rotenone [261]. Expression of Vps35 P316S, which was identified in both patients and controls [258] [262], phenocopied the Vps35 D620N induced cell loss to a lesser extent, Step-wise processing and sub-cellular localization of the Cathepsin D. Following synthesis, Cathepsin D is exported from the ER and subjected to several rounds of enzymatic processing before yielding the lysosomal-localized, light chain peptide (red).…”

Section: Retromer and Parkinson's Diseasementioning

confidence: 99%

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The role of retromer in Parkinson's disease

Follett¹

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Abstract:Parkinson's disease (PD) is an irreversible neurological disorder characterized by protein aggregate accumulation, endo-lysosomal dysfunction and neuronal cell death.Recently, several novel point mutations linked to late onset PD were identified in the retromer subunit; Vps35. Retromer is a highly conserved protein sorting complex that governs the endosome-to-Trans Golgi Network (TGN) trafficking pathway (hereafter referred to as retrograde sorting). While a great deal of evidence currently exists detailing the mechanisms of retromer in the retrograde sorting process, very little information conclusively highlights how sorting is misguided by retromer in PD. Secondly, I identified several novel shortfalls of retromer in the various point mutations that are linked to PD and additionally, expanded on how retromer plays a fundamental role in preservation of the endo-lysosomal network. This thesis demonstrates that Vps35 D620N, Vps35 P316S or Vps35 R524W do not disrupt the overall formation of the retromer complex, but functionally demonstrates incorrect sorting of specific cargo to the TGN. The failed sorting observed by Vps35 D620N containing retromer results in vacuolization of the late endosome, and large disruptions to the overall localization of endocytic compartments. As a result, the lysosomal hydrolase, Cathepsin D, an enzyme needed for the degradation of α-synuclein, is not transported to the late endocytic network and can be detected in the extracellular medium. Subsequent investigation into additional point mutations (Vps35 P316S and Vps35 R524W) highlighted the inability for Vps35 R524W containing retromer to correctly associate with the endosome compartment. While Vps35 P316S containing retromer appears to function identical to that of the wild type retromer, Vps35 R524W negatively regulates retromer-dependent machinery at the endosome surface, leads to the mislocalization of receptors and delays the ability of α-synuclein to be cleared from the cell. Collectively, it is clear that the findings presented here ii strongly implicate the PD-linked Vps35 variants as loss-of-function mutations and lead to the presence of cellular phenotypes witnessed in PD.Lastly, I investigated the use of a pharmacological agent to enhance retromer's function that consequently, aided in significant clearance of α-synuclein inclusions that were observed following the depletion of Vps35 or expression of PD linked mutations Vps35 P316S and Vps35 R524W. These findings support the notion that therapeutic intervention against retromer may aid in delaying the cellular phenotypes observed in PD tissue and subsequently, bridge the gap between the mammalian retromer complex, the lysosome and human disease.iii

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Are we listening to everything the PARK genes are telling us?

Benson

Huntley

2019

J of Comparative Neurology

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The cardinal motor symptoms that define Parkinson's disease (PD) clinically have been recognized for over 200 years. That these symptoms arise following the loss of dopamine neurons in the substantia nigra has been known for the last 50. These long-established facts have fueled a broadly held expectation that degenerating dopaminergic neurons alone hold the key to understanding and curing PD. This prevalent expectation is at odds with the observation that many nonmotor symptoms, including depression and cognitive inflexibility among others, can appear years earlier than the overt dopaminergic neuron degeneration that drives motor abnormalities and are not improved by levodopa treatment. Thus, preserving or rescuing dopamine neuron health and function is of paramount importance, but this alone fails to capture the underlying neurobiology of earlier-appearing nonmotor symptoms. Insight into the complete landscape of disease-related abnormalities and the context in which they arise can be gleaned from a more comprehensive consideration of the PARK genes that are known to cause PD. Here, we make the case that a full incorporation of research showing when and where PARK genes are expressed as well as the impact of gene mutation on function throughout life, in tandem with research studying how dopaminergic neuron degeneration begins, is essential for a full understanding of the multi-dimensional etiology of PD. A broad view may also reveal something about long-term adjustments cells and systems make in response to gene mutation and help to identify mechanisms conferring the resilience or susceptibility of some cells and systems over others. K E Y W O R D Scritical periods, development, nonmotor symptoms, PARK genes, Parkinson's disease, protein degradation, protein trafficking

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In vivo evidence of pathogenicity of VPS35 mutations in the Drosophila

Cited by 40 publications

References 24 publications

The Use of Pharmacological Retromer Chaperones in Alzheimer's Disease and other Endosomal-related Disorders

The Use of Pharmacological Retromer Chaperones in Alzheimer's Disease and other Endosomal-related Disorders

The role of retromer in Parkinson's disease

Are we listening to everything the PARK genes are telling us?

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