Lipid Droplets in the Pathogenesis of Hereditary Spastic Paraplegia

Tadepalle, Nimesha; Rugarli, Elena I.

doi:10.3389/fmolb.2021.673977

Cited by 17 publications

(17 citation statements)

References 161 publications

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“…It has been established that mammalian cells (including both neurons and glia) can accumulate lipid droplets in pathological conditions and in modeling various neurodegenerative disorders, such as Huntington’s and Alzheimer’s disease [ 128 , 129 , 130 , 131 , 132 ], as well as HSP [ 133 , 134 , 135 , 136 ]. Several HSP-associated proteins have been shown to affect LD dynamics: spartin, spastin, atlastin-1, seipin and REEP1 [ 135 , 137 , 138 , 139 , 140 , 141 ]. A recent study has shown that the C-terminal region of NTE/PNPLA6, but not the full-length protein, could also be physically attached to LDs with high affinity, inducing the clustering of the latter [ 142 ].…”

Section: Discussionmentioning

confidence: 99%

Loss of swiss cheese in Neurons Contributes to Neurodegeneration with Mitochondria Abnormalities, Reactive Oxygen Species Acceleration and Accumulation of Lipid Droplets in Drosophila Brain

Melentev

Ryabova

Surina

et al. 2021

IJMS

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Various neurodegenerative disorders are associated with human NTE/PNPLA6 dysfunction. Mechanisms of neuropathogenesis in these diseases are far from clearly elucidated. Hereditary spastic paraplegia belongs to a type of neurodegeneration associated with NTE/PNLPLA6 and is implicated in neuron death. In this study, we used Drosophila melanogaster to investigate the consequences of neuronal knockdown of swiss cheese (sws)—the evolutionarily conserved ortholog of human NTE/PNPLA6—in vivo. Adult flies with the knockdown show longevity decline, locomotor and memory deficits, severe neurodegeneration progression in the brain, reactive oxygen species level acceleration, mitochondria abnormalities and lipid droplet accumulation. Our results suggest that SWS/NTE/PNPLA6 dysfunction in neurons induces oxidative stress and lipid metabolism alterations, involving mitochondria dynamics and lipid droplet turnover in neurodegeneration pathogenesis. We propose that there is a complex mechanism in neurological diseases such as hereditary spastic paraplegia, which includes a stress reaction, engaging mitochondria, lipid droplets and endoplasmic reticulum interplay.

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Section: Discussionmentioning

confidence: 99%

Loss of swiss cheese in Neurons Contributes to Neurodegeneration with Mitochondria Abnormalities, Reactive Oxygen Species Acceleration and Accumulation of Lipid Droplets in Drosophila Brain

Melentev

Ryabova

Surina

et al. 2021

IJMS

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“…However, it recently emerged that dysfunction of one cellular organelle or function can have a deep impact on other cellular functions (Figure 3). For example, proteins implicated in the cytoskeleton dynamics such as spastin, can participate in organellar shaping particularly in ER morphogenesis, or modulate the formation of lipid droplets (LD) which can be considered as the intersection of these pathways with lipid metabolism in the pathogenesis of HSP (Figure 3) (Papadopoulos et al, 2015;Tadepalle and Rugarli, 2021). Furthermore, loss of spatacsin (SPG11) that promotes tubule formation on lysosomes also affects sphingolipid metabolism and leads to impairment of cholesterol recycling from lysosomes resulting in their accumulation and decrease in the cholesterol content of the plasma membrane which allowed us to include SPG11 as the 17th HSP form involving lipid metabolism (Boutry et al, 2018;.…”

Section: Pathways Involved In Hsp Pathogenesismentioning

confidence: 99%

“…[AR: ichthyotic keratoderma, spasticity, hypomyelination and dysmorphic features (IKSHD)], ELOVL4 [AR: ichthyosis, intellectual disability and spastic quadriplegia (ISQMR); AD: SCA34, Stargardt disease 3 ((STGD3)], ALDH3A2 [Sjögren-Larsson Syndrome (SLS)]. This long list of examples provides clear evidence that the existing phenotypic classes of neurogenetic disorders need to be reconsidered Tadepalle and Rugarli, 2021). Various types of lipids are involved in spastic neurodegeneration including precursor lipids as cholesterol and fatty acids as well as complex lipids like phospholipids and sphingolipids.…”

Section: Pathways Involved In Hsp Pathogenesismentioning

confidence: 99%

“…Various types of lipids are involved in spastic neurodegeneration including precursor lipids as cholesterol and fatty acids as well as complex lipids like phospholipids and sphingolipids. Disturbed biosynthesis and degradation of these lipids can lead to either deficiencies of molecules with functional importance, or pathogenic accumulation of precursors or undegraded damaged molecules with toxic effect, all resulting in neurodegeneration Tadepalle and Rugarli, 2021).…”

Section: Pathways Involved In Hsp Pathogenesismentioning

confidence: 99%

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Insights into Clinical, Genetic, and Pathological Aspects of Hereditary Spastic Paraplegias: A Comprehensive Overview

Elsayed

Eltazi

Ahmed

et al. 2021

Front. Mol. Biosci.

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Hereditary spastic paraplegias (HSP) are a heterogeneous group of motor neurodegenerative disorders that have the core clinical presentation of pyramidal syndrome which starts typically in the lower limbs. They can present as pure or complex forms with all classical modes of monogenic inheritance reported. To date, there are more than 100 loci/88 spastic paraplegia genes (SPG) involved in the pathogenesis of HSP. New patterns of inheritance are being increasingly identified in this era of huge advances in genetic and functional studies. A wide range of clinical symptoms and signs are now reported to complicate HSP with increasing overall complexity of the clinical presentations considered as HSP. This is especially true with the emergence of multiple HSP phenotypes that are situated in the borderline zone with other neurogenetic disorders. The genetic diagnostic approaches and the utilized techniques leave a diagnostic gap of 25% in the best studies. In this review, we summarize the known types of HSP with special focus on those in which spasticity is the principal clinical phenotype (“SPGn” designation). We discuss their modes of inheritance, clinical phenotypes, underlying genetics, and molecular pathways, providing some observations about therapeutic opportunities gained from animal models and functional studies. This review may pave the way for more analytic approaches that take into consideration the overall picture of HSP. It will shed light on subtle associations that can explain the occurrence of the disease and allow a better understanding of its observed variations. This should help in the identification of future biomarkers, predictors of disease onset and progression, and treatments for both better functional outcomes and quality of life.

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“…Several lines of evidence have identified lipid homeostasis disruption in cellular and animal models of HSP (reviewed in [ 19 , 84 ]). To examine whether Arl6IP1 functionally contributes to lipid homeostasis in vivo, we investigated LD organisation within axonal bundles of control and Arl6IP1 KO flies.…”

Section: Resultsmentioning

confidence: 99%

Liver X receptor-agonist treatment rescues degeneration in a Drosophila model of hereditary spastic paraplegia

Byrne

Garcia-Pardo

Cole

et al. 2022

acta neuropathol commun

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Hereditary spastic paraplegias (HSPs) are a group of inherited, progressive neurodegenerative conditions characterised by prominent lower-limb spasticity and weakness, caused by a length-dependent degeneration of the longest corticospinal upper motor neurons. While more than 80 spastic paraplegia genes (SPGs) have been identified, many cases arise from mutations in genes encoding proteins which generate and maintain tubular endoplasmic reticulum (ER) membrane organisation. The ER-shaping proteins are essential for the health and survival of long motor neurons, however the mechanisms by which mutations in these genes cause the axonopathy observed in HSP have not been elucidated. To further develop our understanding of the ER-shaping proteins, this study outlines the generation of novel in vivo and in vitro models, using CRISPR/Cas9-mediated gene editing to knockout the ER-shaping protein ADP-ribosylation factor-like 6 interacting protein 1 (ARL6IP1), mutations in which give rise to the HSP subtype SPG61. Loss of Arl6IP1 in Drosophila results in progressive locomotor deficits, emulating a key aspect of HSP in patients. ARL6IP1 interacts with ER-shaping proteins and is required for regulating the organisation of ER tubules, particularly within long motor neuron axons. Unexpectedly, we identified physical and functional interactions between ARL6IP1 and the phospholipid transporter oxysterol-binding protein-related protein 8 in both human and Drosophila model systems, pointing to a conserved role for ARL6IP1 in lipid homeostasis. Furthermore, loss of Arl6IP1 from Drosophila neurons results in a cell non-autonomous accumulation of lipid droplets in axonal glia. Importantly, treatment with lipid regulating liver X receptor-agonists blocked lipid droplet accumulation, restored axonal ER organisation, and improved locomotor function in Arl6IP1 knockout Drosophila. Our findings indicate that disrupted lipid homeostasis contributes to neurodegeneration in HSP, identifying a potential novel therapeutic avenue for the treatment of this disorder.

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Lipid Droplets in the Pathogenesis of Hereditary Spastic Paraplegia

Cited by 17 publications

References 161 publications

Loss of swiss cheese in Neurons Contributes to Neurodegeneration with Mitochondria Abnormalities, Reactive Oxygen Species Acceleration and Accumulation of Lipid Droplets in Drosophila Brain

Loss of swiss cheese in Neurons Contributes to Neurodegeneration with Mitochondria Abnormalities, Reactive Oxygen Species Acceleration and Accumulation of Lipid Droplets in Drosophila Brain

Insights into Clinical, Genetic, and Pathological Aspects of Hereditary Spastic Paraplegias: A Comprehensive Overview

Liver X receptor-agonist treatment rescues degeneration in a Drosophila model of hereditary spastic paraplegia

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