Lipid Droplets in Neurodegenerative Disorders

Farmer, Brandon C.; Walsh, Adeline E.; Kluemper, Jude C.; Johnson, Lance A.

doi:10.3389/fnins.2020.00742

Cited by 185 publications

(187 citation statements)

References 131 publications

(139 reference statements)

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“…Our results also imply that conditions affecting the LD formation/dissolution equilibrium affect Nup dynamics. This may include high fat intake ( Figure 4 A, [ 9 ]), stresses boosting LD formation [ 93 , 94 ], obesity [ 95 ], aging [ 96 , 97 ], or degenerative diseases [ 98 ]. Furthermore, Nup dynamics is greatly affected by genetic alterations, as illustrated by cds1 and fld1 cells, which modify the surface and the physico-chemical properties of the LD monolayer.…”

Section: Discussionmentioning

confidence: 99%

Lipid Droplets Are a Physiological Nucleoporin Reservoir

Kumanski

Viart

Kossida

et al. 2021

Cells

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Lipid Droplets (LD) are dynamic organelles that originate in the Endoplasmic Reticulum and mostly bud off toward the cytoplasm, where they store neutral lipids for energy and protection purposes. LD also have diverse proteins on their surface, many of which are necessary for the their correct homeostasis. However, these organelles also act as reservoirs of proteins that can be made available elsewhere in the cell. In this sense, they act as sinks that titrate key regulators of many cellular processes. Among the specialized factors that reside on cytoplasmic LD are proteins destined for functions in the nucleus, but little is known about them and their impact on nuclear processes. By screening for nuclear proteins in publicly available LD proteomes, we found that they contain a subset of nucleoporins from the Nuclear Pore Complex (NPC). Exploring this, we demonstrate that LD act as a physiological reservoir, for nucleoporins, that impacts the conformation of NPCs and hence their function in nucleo-cytoplasmic transport, chromatin configuration, and genome stability. Furthermore, our in silico modeling predicts a role for LD-released fatty acids in regulating the transit of nucleoporins from LD through the cytoplasm and to nuclear pores.

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Section: Discussionmentioning

confidence: 99%

Lipid Droplets Are a Physiological Nucleoporin Reservoir

Kumanski

Viart

Kossida

et al. 2021

Cells

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“…Finally, lipid biogenesis can be disrupted by alterations to mitochondrial fission/fusion. Within the nervous system, lipid droplets (LDs) play vital roles in energy storage, glia-neuron communication and ROS management and lipid homeostasis is necessary for maintaining neuronal function and synaptic plasticity [60]. Defective mitochondrial fusion causes an accumulation of neutral lipids within lipid droplets in both mitofusin 1 knockout cells and fibroblasts from Charcot-Marie-Tooth disease (CMT) type 2A patients [61,62].…”

Section: Discussionmentioning

confidence: 99%

Loss of the Mitochondrial Fission GTPase Drp1 Contributes to Neurodegeneration in a Drosophila Model of Hereditary Spastic Paraplegia

et al. 2020

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Mitochondrial morphology, distribution and function are maintained by the opposing forces of mitochondrial fission and fusion, the perturbation of which gives rise to several neurodegenerative disorders. The large guanosine triphosphate (GTP)ase dynamin-related protein 1 (Drp1) is a critical regulator of mitochondrial fission by mediating membrane scission, often at points of mitochondrial constriction at endoplasmic reticulum (ER)-mitochondrial contacts. Hereditary spastic paraplegia (HSP) subtype SPG61 is a rare neurodegenerative disorder caused by mutations in the ER-shaping protein Arl6IP1. We have previously reported defects in both the ER and mitochondrial networks in a Drosophila model of SPG61. In this study, we report that knockdown of Arl6IP1 lowers Drp1 protein levels, resulting in reduced ER–mitochondrial contacts and impaired mitochondrial load at the distal ends of long motor neurons. Increasing mitochondrial fission, by overexpression of wild-type Drp1 but not a dominant negative Drp1, increases ER–mitochondrial contacts, restores mitochondrial load within axons and partially rescues locomotor deficits. Arl6IP1 knockdown Drosophila also demonstrate impaired autophagic flux and an accumulation of ubiquitinated proteins, which occur independent of Drp1-mediated mitochondrial fission defects. Together, these findings provide evidence that impaired mitochondrial fission contributes to neurodegeneration in this in vivo model of HSP.

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“…Moreover, accumulation of the lipid droplets related to aging in myocardial cells of the rat (Travis & Travis, 1972) and multiple regions of human and rodent brains has been reported (Brawer & Walsh, 1982; Marschallinger et al, 2020; Shimabukuro et al, 2016). Thus it is probable that, like for lipofuscin granules, the accumulation of lipid droplets is a hallmark of age (Farmer et al, 2020). Indeed, accumulation of both lipofuscin granules (Brunk & Terman, 2002; König et al, 2017) and lipid droplets (Liu et al, 2015) is related to oxidative stress and mitochondrial dysfunction.…”

Section: Discussionmentioning

confidence: 99%

Structural and ultrastructural studies on the developing vomeronasal sensory epithelium in the grass snake Natrix natrix (Squamata: Colubroidea)

Kaczmarek

Rupik

2020

Journal of Morphology

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The sensory olfactory epithelium and the vomeronasal sensory epithelium (VSE) are characterized by continuous turnover of the receptor cells during postnatal life and are capable of regeneration after injury. The VSE, like the entire vomeronasal organ, is generally well developed in squamates and is crucial for detection of pheromones and prey odors. Despite the numerous studies on embryonic development of the VSE in squamates, especially in snakes, an ultrastructural analysis, as far as we know, has never been performed. Therefore, we investigated the embryology of the VSE of the grass snake (Natrix natrix) using electron microscopy (SEM and TEM) and light microscopy. As was shown for adult snakes, the hypertrophied ophidian VSE may provide great resolution of changes in neuron morphology located at various epithelial levels. The results of this study suggest that different populations of stem/progenitor cells occur at the base of the ophidian VSE during embryonic development. One of them may be radial glia‐like cells, described previously in mouse. The various structure and ultrastructure of neurons located at different parts of the VSE provide evidence for neuronal maturation and aging. Based on these results, a few nonmutually exclusive hypotheses explaining the formation of the peculiar columnar organization of the VSE in snakes were proposed.

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Lipid Droplets in Neurodegenerative Disorders

Cited by 185 publications

References 131 publications

Lipid Droplets Are a Physiological Nucleoporin Reservoir

Lipid Droplets Are a Physiological Nucleoporin Reservoir

Loss of the Mitochondrial Fission GTPase Drp1 Contributes to Neurodegeneration in a Drosophila Model of Hereditary Spastic Paraplegia

Structural and ultrastructural studies on the developing vomeronasal sensory epithelium in the grass snake Natrix natrix (Squamata: Colubroidea)

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