Stress-Induced Cellular Clearance Is Mediated by the SNARE Protein ykt6 and Disrupted by α-Synuclein

Cuddy, Leah K.; Wani, Willayat Yousuf; Morella, Martino L; Pitcairn, Caleb; Tsutsumi, Kotaro; Fredriksen, Kristina; Justman, Craig J.; Grammatopoulos, Tom N.; Belur, Nandkishore R.; Zunke, Friederike; Subramanian, Aarthi; Affaneh, Amira; Lansbury, Peter T.; Mazzulli, Joseph R.

doi:10.1016/j.neuron.2019.09.001

Cited by 53 publications

(69 citation statements)

References 77 publications

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“…A second group found that αS impairs trafficking of hydrolases to lysosomes by inhibiting the function of the SNARE protein ykt6 53 . Ykt6 is regulated by both palmitoylation and farnesylation in a unique manner.…”

Section: Discussionmentioning

confidence: 99%

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Upregulation of Cellular Palmitoylation Mitigates α‐Synuclein Accumulation and Neurotoxicity

Ramalingam

Imberdis

et al. 2020

Movement Disorders

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Background Synucleinopathies, including Parkinson's disease (PD), are characterized by α‐synuclein (αS) cytoplasmic inclusions. αS‐dependent vesicle‐trafficking defects are important in PD pathogenesis, but their mechanisms are not well understood. Protein palmitoylation, post‐translational addition of the fatty acid palmitate to cysteines, promotes trafficking by anchoring specific proteins to the vesicle membrane. αS itself cannot be palmitoylated as it lacks cysteines, but it binds to membranes, where palmitoylation occurs, via an amphipathic helix. We hypothesized that abnormal αS membrane‐binding impairs trafficking by disrupting palmitoylation. Accordingly, we investigated the therapeutic potential of increasing cellular palmitoylation. Objectives We asked whether upregulating palmitoylation by inhibiting the depalmitoylase acyl‐protein‐thioesterase‐1 (APT1) ameliorates pathologic αS‐mediated cellular phenotypes and sought to identify the mechanism. Methods Using human neuroblastoma cells, rat neurons, and iPSC‐derived PD patient neurons, we examined the effects of pharmacologic and genetic downregulation of APT1 on αS‐associated phenotypes. Results APT1 inhibition or knockdown decreased αS cytoplasmic inclusions, reduced αS serine‐129 phosphorylation (a PD neuropathological marker), and protected against αS‐dependent neurotoxicity. We identified the APT1 substrate microtubule‐associated‐protein‐6 (MAP6), which binds to vesicles in a palmitoylation‐dependent manner, as a key mediator of these effects. Mechanistically, we found that pathologic αS accelerated palmitate turnover on MAP6, suggesting that APT1 inhibition corrects a pathological αS‐dependent palmitoylation deficit. We confirmed the disease relevance of this mechanism by demonstrating decreased MAP6 palmitoylation in neurons from αS gene triplication patients. Conclusions Our findings demonstrate a novel link between the fundamental process of palmitoylation and αS pathophysiology. Upregulating palmitoylation represents an unexplored therapeutic strategy for synucleinopathies. © 2020 International Parkinson and Movement Disorder Society

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Section: Discussionmentioning

confidence: 99%

“…Subsequent palmitoylation of an adjacent cysteine then permits adoption of an “open” conformation, membrane association, and SNARE activity 55 . Farnesyltransferase inhibitors restored ykt6‐dependent hydrolase trafficking 53 . The influence of palmitoylation on ykt6 was not explored.…”

Section: Discussionmentioning

confidence: 99%

Upregulation of Cellular Palmitoylation Mitigates α‐Synuclein Accumulation and Neurotoxicity

Ramalingam

Imberdis

et al. 2020

Movement Disorders

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“…GluCer-induced aSyn forms have also been directly associated with endogenous neurotoxicity, as well as decreased neuronal viability upon endocytosis from healthy DAergic neurons ( Zunke et al, 2018 ). An equally important aspect of the aSyn–GCase interaction is that increased aSyn levels can per se impair lysosomal GCase activity via improper enzyme maturation and trafficking, an effect that also disrupts other lysosomal enzymes ( Mazzulli et al, 2016a ; Cuddy et al, 2019 ). Specifically, aSyn disrupts the association between the SNARE protein ykt6, implicated in ER–Golgi trafficking, and membranes, validated in iPSC-derived DAergic neurons from SNCA triplication- or A53T aSyn PD patients ( Cuddy et al, 2019 ).…”

Section: Lysosomal Dysfunction and Alpha-synuclein Linked By Glucocermentioning

confidence: 99%

“…An equally important aspect of the aSyn–GCase interaction is that increased aSyn levels can per se impair lysosomal GCase activity via improper enzyme maturation and trafficking, an effect that also disrupts other lysosomal enzymes ( Mazzulli et al, 2016a ; Cuddy et al, 2019 ). Specifically, aSyn disrupts the association between the SNARE protein ykt6, implicated in ER–Golgi trafficking, and membranes, validated in iPSC-derived DAergic neurons from SNCA triplication- or A53T aSyn PD patients ( Cuddy et al, 2019 ). Further mechanistic investigations in iPSC-derived DAergic neurons have revealed that some PD-associated proteins exert an inhibitory effect on GCase activity that can, at least partly, be attributed to DA oxidation.…”

Section: Lysosomal Dysfunction and Alpha-synuclein Linked By Glucocermentioning

confidence: 99%

“…Alternatively, promoting wild-type GCase activity (10 days, compound S-181) successfully reduced glucolipids and DA/aSyn pathological phenotypes in LRRK2 , DJ-1 , and PARKIN as well as sporadic PD long-term iPSC-derived DAergic cultures (up to day 160) ( Burbulla et al, 2019 ). Furthermore, application of a farnesyltransferase inhibitor (LNK-754) could also promote GCase lysosomal translocation by promoting the ykt6–Golgi membrane interaction, reducing pathological aSyn in SNCA -PD DAergic neurons ( Cuddy et al, 2019 ). Indirect targeting of GCase activity includes pharmacological or genetic LRRK2 inhibition, assessed in GBA1- and LRRK2- PD iPSC-derived DAergic neurons ( Nguyen and Krainc, 2018 ; Ysselstein et al, 2019 ).…”

Section: Disease-modifying Therapies For Pdmentioning

confidence: 99%

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The Convergence of Alpha-Synuclein, Mitochondrial, and Lysosomal Pathways in Vulnerability of Midbrain Dopaminergic Neurons in Parkinson’s Disease

Minakaki

Krainc

Burbulla

2020

Front. Cell Dev. Biol.

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Parkinson’s disease (PD) is the second most common neurodegenerative disease, characterized by progressive bradykinesia, rigidity, resting tremor, and gait impairment, as well as a spectrum of non-motor symptoms including autonomic and cognitive dysfunction. The cardinal motor symptoms of PD stem from the loss of substantia nigra (SN) dopaminergic (DAergic) neurons, and it remains unclear why SN DAergic neurons are preferentially lost in PD. However, recent identification of several genetic PD forms suggests that mitochondrial and lysosomal dysfunctions play important roles in the degeneration of midbrain dopamine (DA) neurons. In this review, we discuss the interplay of cell-autonomous mechanisms linked to DAergic neuron vulnerability and alpha-synuclein homeostasis. Emerging studies highlight a deleterious feedback cycle, with oxidative stress, altered DA metabolism, dysfunctional lysosomes, and pathological alpha-synuclein species representing key events in the pathogenesis of PD. We also discuss the interactions of alpha-synuclein with toxic DA metabolites, as well as the biochemical links between intracellular iron, calcium, and alpha-synuclein accumulation. We suggest that targeting multiple pathways, rather than individual processes, will be important for developing disease-modifying therapies. In this context, we focus on current translational efforts specifically targeting lysosomal function, as well as oxidative stress via calcium and iron modulation. These efforts could have therapeutic benefits for the broader population of sporadic PD and related synucleinopathies.

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The role of lysosomal cathepsins in neurodegeneration: Mechanistic insights, diagnostic potential and therapeutic approaches

Drobny¹,

Huarcaya²,

Dobert³

et al. 2022

Biochimica et Biophysica Acta (BBA) - Molecular Cell Research

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Stress-Induced Cellular Clearance Is Mediated by the SNARE Protein ykt6 and Disrupted by α-Synuclein

Cited by 53 publications

References 77 publications

Upregulation of Cellular Palmitoylation Mitigates α‐Synuclein Accumulation and Neurotoxicity

Upregulation of Cellular Palmitoylation Mitigates α‐Synuclein Accumulation and Neurotoxicity

The Convergence of Alpha-Synuclein, Mitochondrial, and Lysosomal Pathways in Vulnerability of Midbrain Dopaminergic Neurons in Parkinson’s Disease

The role of lysosomal cathepsins in neurodegeneration: Mechanistic insights, diagnostic potential and therapeutic approaches

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