VPS35 Deficiency or Mutation Causes Dopaminergic Neuronal Loss by Impairing Mitochondrial Fusion and Function

Tang, Fu Lei; Liu, Wei; Jin, Haixia; Erion, Joanna; Ye, Jian; Mei, Lin; Xiong, Wen-Cheng

doi:10.1016/j.celrep.2015.08.001

Cited by 228 publications

(289 citation statements)

References 43 publications

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“…Targeted deletion of VPS35 in mice caused fragmented mitochondria as a result of increased mitochondrial E3 ubiquitin ligase 1 activity and consequent degradation of Mfn2 (Tang et al, 2015). Importantly, stabilization of Mfn2 in the VPS35-deletion model could prevent the loss of dopaminergic neurons (Tang et al, 2015).…”

Section: (2) Additional Neurodegenerative Diseasesmentioning

confidence: 99%

“…In addition, Mfn2 has been implicated in the function of the retromer component vacuolar protein sorting-35 (VPS35), mutations of which are linked to familial PD (Vilarino-Guell et al, 2011;Zimprich et al, 2011) and also associated with AD (Small et al, 2005;Muhammad et al, 2008). Targeted deletion of VPS35 in mice caused fragmented mitochondria as a result of increased mitochondrial E3 ubiquitin ligase 1 activity and consequent degradation of Mfn2 (Tang et al, 2015). Importantly, stabilization of Mfn2 in the VPS35-deletion model could prevent the loss of dopaminergic neurons (Tang et al, 2015).…”

Section: (2) Additional Neurodegenerative Diseasesmentioning

confidence: 99%

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Structure, function, and regulation of mitofusin‐2 in health and disease

2017

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Mitochondria are highly dynamic organelles that constantly migrate, fuse, and divide to regulate their shape, size, number, and bioenergetic function. Mitofusins (Mfn1/2), optic atrophy 1 (OPA1), and dynamin-related protein 1 (Drp1), are key regulators of mitochondrial fusion and fission. Mutations in these molecules are associated with severe neurodegenerative and non-neurological diseases pointing to the importance of functional mitochondrial dynamics in normal cell physiology. In recent years, significant progress has been made in our understanding of mitochondrial dynamics, which has raised interest in defining the physiological roles of key regulators of fusion and fission and led to the identification of additional functions of Mfn2 in mitochondrial metabolism, cell signalling, and apoptosis. In this review, we summarize the current knowledge of the structural and functional properties of Mfn2 as well as its regulation in different tissues, and also discuss the consequences of aberrant Mfn2 expression.

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Section: (2) Additional Neurodegenerative Diseasesmentioning

confidence: 99%

Section: (2) Additional Neurodegenerative Diseasesmentioning

confidence: 99%

Structure, function, and regulation of mitofusin‐2 in health and disease

2017

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“…Despite these data, it cannot be excluded that CNVs in VPS35 maybe occur in other PD patients groups and contribute to PD onset. It has very recently demonstrated that specific deletion of VPS35 in dopaminergic neurons of deficient mice resulted in PD-like deficits including loss of dopaminergic neurons and accumulation of alpha-synuclein [110].…”

Section: Vps35mentioning

confidence: 99%

Genetics of Parkinson’s Disease: The Role of Copy Number Variations

Cognata¹,

D’Agata²,

Cavalcanti³

et al. 2016

Challenges in Parkinson's Disease

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Parkinson's disease (PD), the second most common progressive neurodegenerative disorder, was long believed to be a non-genetic sporadic origin syndrome. The identification of distinct genetic loci responsible for rare Mendelian forms of PD has represented a revolutionary breakthrough, allowing to discover novel mechanisms underlying this debilitating still incurable condition. Along with single-nucleotide polymorphisms (SNPs), other kinds of DNA molecular defects have emerged as significant disease-causing mutations, including large chromosomic structural rearrangements and copy number variations (CNVs). Due to their size variability and to the different sensitivity and resolution of detection methodologies, CNVs constitute a particular challenge in genetic studies and the pathogenetic or susceptibility impact of specific CNVs on PD is currently under debate. In this chapter, we will review the current literature and bioinformatic data describing the involvement of CNVs on PD pathobiology. We will discuss the recently highlighted role of PARK2 heterozygous CNVs, the possible common founder effects of PD gene rearrangements and the importance to map genetic breakpoints. We will also add a summary about the current available molecular methods and bioinformatics web resources to detect and interpret CNVs. Assessing the global genome-wide burden of large CNVs and elucidating the role of de novo rare structural variants on PD may reveal new candidate genes and consequently ameliorate diagnosis and counselling of mutations carriers.

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“…A recent study has demonstrated that VPS35 depletion in mouse dopamine neurons induces a PD-like condition, including neuronal death, α-synuclein deposition and fragmented mitochondria (Tang et al, 2015). VPS35 depletion or mutation also led to increased levels of the ubiquitin ligase Mul1, which ubiquitylates Mfn2 on the mitochondrial membrane, induces its proteasomal degradation, and may thus promote increased fission-to-fusion and fragmented mitochondria (Tang et al, 2015). Alternatively (or in parallel), a second study provides support for a different model for VPS35 function in the regulation of mitochondrial homeostasis and PD.…”

Section: Introductionmentioning

confidence: 99%

“…Mitochondrial function is closely controlled by their dynamics, and they are continually undergoing cycles of fusion and fission, processes required for homeostasis and mitochondrial health (Chan, 2012). Indeed, perturbations of mitochondrial dynamics have been documented in a wide variety of neurodegenerative disorders, including Alzheimer's disease (Cho et al, 2009) and Parkinson's disease (PD) (Tang et al, 2015). Although the specific mechanisms by which mitochondrial dynamics influence many neurological disorders remain unclear, fusion and fission control mitochondrial size and shape, the number of mitochondria for inheritance in dividing cells, and many mitochondrial functions, such as respiration, cell survival, etc.…”

Section: Introductionmentioning

confidence: 99%

Control of mitochondrial homeostasis by endocytic regulatory proteins

Farmer

Reinecke

Xie

et al. 2017

Journal of Cell Science

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Mitochondria play essential roles in cellular energy processes, including ATP production, control of reactive oxygen species (ROS) and apoptosis. While mitochondrial function is regulated by the dynamics of fusion and fission, mitochondrial homeostasis remains incompletely understood. Recent studies implicate dynamin-2 and dynamin-related protein-1 (Drp1, also known as DNM1L), as GTPases involved in mitochondrial fission. Here, we identify the ATPase and endocytic protein EHD1 as a novel regulator of mitochondrial fission. EHD1 depletion induces a static and elongated network of mitochondria in the cell. However, unlike dynamin-2 and Drp1, whose depletion protects cells from staurosporine-induced mitochondrial fragmentation, EHD1-depleted cells remain sensitive to staurosporine, suggesting a different mechanism for EHD1 function. Recent studies have demonstrated that VPS35 and the retromer complex influence mitochondrial homeostasis either by Mul1-mediated ubiquitylation and degradation of the fusion protein Mfn2, or by removal of inactive Drp1 from the mitochondrial membrane. We demonstrate that EHD1 and its interaction partner rabankyrin-5 interact with the retromer complex to influence mitochondrial dynamics, likely by inducing VPS35-mediated removal of inactive Drp1 from mitochondrial membranes. Our study sheds light on mitochondrial dynamics, expanding a new paradigm of endocytic protein regulation of mitochondrial homeostasis.

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VPS35 Deficiency or Mutation Causes Dopaminergic Neuronal Loss by Impairing Mitochondrial Fusion and Function

Cited by 228 publications

References 43 publications

Structure, function, and regulation of mitofusin‐2 in health and disease

Structure, function, and regulation of mitofusin‐2 in health and disease

Genetics of Parkinson’s Disease: The Role of Copy Number Variations

Control of mitochondrial homeostasis by endocytic regulatory proteins

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