LRRK2-mediated phosphorylation of HDAC6 regulates HDAC6-cytoplasmic dynein interaction and aggresome formation

Lucas, Richard M.; Bauer, Claudia S.; Chinnaiya, Kavitha; Schwartzentruber, Aurelie; MacDonald, Robert C.; Collins, Mark O.; Aasly, Jan; Brønstad, Gunnar; Ferraiuolo, Laura; Mortiboys, Heather; Vos, Kurt J. De

doi:10.1101/554881

Cited by 3 publications

(1 citation statement)

References 43 publications

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“…Aggresomes are a regulated response to misfolded proteins and proteasomal inhibition, typically in stressed cells, in which proteins are trafficked along microtubules to the microtubule organising complex by dynein motor proteins [33]. HDAC6 interacts with the dynein motor protein to transport misfolded proteins to the aggresome through the microtubule network [27], and interactions with dynein are enhanced by phosphorylation of HDAC6 at serine 22 (HDAC6 pS22) [34]. Thus, our observation that HDAC6 pS22 is enriched within Lewy bodies is consistent with the constituent components of Lewy bodies having been trafficked there via the microtubule network.…”

Section: Discussionmentioning

confidence: 99%

Autophagic cargo in Lewy bodies: are Lewy bodies a compartment for spatial protein quality control?

Conod,

Charlesworth,

Palmowski

et al. 2023

Preprint

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Lewy bodies are neuropathologically associated with Lewy body dementia (LBD), but little is known about why they form or their role in the disease process. We previously reported Lewy bodies are a common feature of older individuals with primary mitochondrial diseases. However, as they are not an invariant finding, understanding differences between those with and without Lewy bodies may provide insights into factors that govern the formation of Lewy bodies in Lewy body disease (LBD). The present study sought to investigate whether deficient mitophagy in the context of mitochondrial dysfunction may underlie Lewy body formation. Post-mortem tissue was obtained from the cingulate gyrus and dorsal motor nucleus of the vagal nerve (DMV) of mitochondrial disease cases with Lewy bodies, primary mitochondrial disease cases without Lewy bodies, and control cases, in addition to LBD cases as comparison. An array of mitophagy and autophagy markers were quantified in 50 individual neurons per cingulate gyrus and all neurons per DMV using immunofluorescent analysis. No significant differences were found between groups, although there was a striking enrichment of markers of autophagic mitochondria and autophagic vesicles within Lewy bodies. Evaluation of diffuse α-synuclein aggregates, thought to precede Lewy body formation, suggested only autophagic mitochondria were present in early aggregates, perhaps suggesting sequestration of dysfunctional mitochondria is an early step in Lewy body formation. To characterise the composition of Lewy bodies, discovery proteomics was performed on isolated insoluble proteins from frozen cingulate gyrus, which identified up-regulation of markers of aggresomes, a regulated cellular response that occurs when protein degradative pathways become overwhelmed, a mechanism of spatial protein quality control (sPQC). Taken together, these findings are consistent with impairment of cellular waste handling pathways in Lewy body-bearing neurons, and that the formation of a Lewy body could be a deliberate cellular response to compartmentalise such waste.

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Section: Discussionmentioning

confidence: 99%

Autophagic cargo in Lewy bodies: are Lewy bodies a compartment for spatial protein quality control?

Conod,

Charlesworth,

Palmowski

et al. 2023

Preprint

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Dynamic control of the dopamine transporter in neurotransmission and homeostasis

Farrer

Khoshbouei

2021

npj Parkinsons Dis.

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The dopamine transporter (DAT) transports extracellular dopamine into the intracellular space contributing to the regulation of dopamine neurotransmission. A reduction of DAT density is implicated in Parkinson’s disease (PD) by neuroimaging; dopamine turnover is dopamine turnover is elevated in early symptomatic PD and in presymptomatic individuals with monogenic mutations causal for parkinsonism. As an integral plasma membrane protein, DAT surface expression is dynamically regulated through endocytic trafficking, enabling flexible control of dopamine signaling in time and space, which in turn critically modulates movement, motivation and learning behavior. Yet the cellular machinery and functional implications of DAT trafficking remain enigmatic. In this review we summarize mechanisms governing DAT trafficking under normal physiological conditions and discuss how PD-linked mutations may disturb DAT homeostasis. We highlight the complexity of DAT trafficking and reveal DAT dysregulation as a common theme in genetic models of parkinsonism.

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A dual inhibitor targeting HMG-CoA reductase and histone deacetylase mitigates neurite degeneration in LRRK2-G2019S parkinsonism

Lin

Fang

et al. 2020

Aging

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LRRK2-mediated phosphorylation of HDAC6 regulates HDAC6-cytoplasmic dynein interaction and aggresome formation

Cited by 3 publications

References 43 publications

Autophagic cargo in Lewy bodies: are Lewy bodies a compartment for spatial protein quality control?

Autophagic cargo in Lewy bodies: are Lewy bodies a compartment for spatial protein quality control?

Dynamic control of the dopamine transporter in neurotransmission and homeostasis

A dual inhibitor targeting HMG-CoA reductase and histone deacetylase mitigates neurite degeneration in LRRK2-G2019S parkinsonism

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