Cholesterol and multilamellar bodies: Lysosomal dysfunction in <i>GBA</i>-Parkinson disease

García‐Sanz, Patricia; Orgaz, Lorena; Fuentes, José; Vicario‐Abejón, Carlos; Moratalla, Rosario

doi:10.1080/15548627.2018.1427396

Cited by 59 publications

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“…Likewise, a-Syn aggregates might impair the autophagic-lysosomal pathway function (Xilouri et al, 2013a), establishing a reciprocal relationship. The accumulation of a-Syn reduces lysosomal degradation capacity b y d i s r u p t i n g h y d r o l a s e s t r a ffi c k i n g , s u c h a s o f glucocerebrosidase 1 (GCase1), from the endoplasmic reticulum to the lysosome (Mazzulli et al, 2011;García-Sanz et al, 2017;García-Sanz et al, 2018). Currently, mutations in the GBA1 gene are the main genetic risk factor for PD.…”

Section: Propagation Of Alpha-synuclein: Evidence and Considerationsmentioning

confidence: 99%

“…GBA1 mutations result in reduced enzymatic activity that leads to the accumulation of glucosylceramide and of cholesterol and its esters in lysosomes, which can compromise lysosomal function and promote a-Syn aggregation, creating a bidirectional loop (Schapira, 2015). Previous studies from our laboratory have shown that fibroblasts derived from PD patients with the GBA1 mutation accumulate cholesterol in lysosomes and present multilamellar bodies (García-Sanz et al, 2017;García-Sanz et al, 2018). Also, membrane structures resembling lysosomes and autophagosomes have been found in the inner architecture of Lewy bodies (Shahmoradian et al, 2019), suggesting that the alteration of these organelles might contribute to the formation of Lewy bodies.…”

Section: Propagation Of Alpha-synuclein: Evidence and Considerationsmentioning

confidence: 99%

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Modeling Parkinson’s Disease With the Alpha-Synuclein Protein

et al. 2020

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Alpha-synuclein (a-Syn) is a key protein involved in Parkinson's disease (PD) pathology. PD is characterized by the loss of dopaminergic neuronal cells in the substantia nigra pars compacta and the abnormal accumulation and aggregation of a-Syn in the form of Lewy bodies and Lewy neurites. More precisely, the aggregation of a-Syn is associated with the dysfunctionality and degeneration of neurons in PD. Moreover, mutations in the SNCA gene, which encodes a-Syn, cause familial forms of PD and are the basis of sporadic PD risk. Given the role of the a-Syn protein in the pathology of PD, animal models that reflect the dopaminergic neuronal loss and the widespread and progressive formation of a-Syn aggregates in different areas of the brain constitute a valuable tool. Indeed, animal models of PD are important for understanding the molecular mechanisms of the disease and might contribute to the development and validation of new therapies. In the absence of animal models that faithfully reproduce human PD, in recent years, numerous animal models of PD based on a-Syn have been generated. In this review, we summarize the main features of the a-Syn pre-formed fibrils (PFFs) model and recombinant adenoassociated virus vector (rAAV) mediated a-Syn overexpression models, providing a detailed comparative analysis of both models. Here, we discuss how each model has contributed to our understanding of PD pathology and the advantages and weakness of each of them. Significance: Here, we show that injection of a-Syn PFFs and overexpression of a-Syn mediated by rAAV lead to a different pattern of PD pathology in rodents. First, a-Syn PFFs models trigger the Lewy body-like inclusions formation in brain regions directly interconnected with the injection site, suggesting that there is an inter-neuronal transmission of the a-Syn pathology. In contrast, rAAV-mediated a-Syn overexpression in the brain limits the a-Syn aggregates within the transduced neurons. Second, phosphorylated a-Syn inclusions obtained with rAAV are predominantly nuclear with a punctate appearance that becomes diffuse along the neuronal fibers, whereas a-Syn PFFs models lead to the formation of cytoplasmic aggregates of phosphorylated a-Syn reminiscent of Lewy bodies and Lewy neurites.

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Section: Propagation Of Alpha-synuclein: Evidence and Considerationsmentioning

confidence: 99%

Section: Propagation Of Alpha-synuclein: Evidence and Considerationsmentioning

confidence: 99%

Modeling Parkinson’s Disease With the Alpha-Synuclein Protein

et al. 2020

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“…The accumulated MLBs have been proposed to be related to deficiency of fusion of autophagosomes with lysosomes or/and lysosomal disorders, 57,58 which eventually disturbs autophagy flux. 58,[85][86][87] It appears that there are potentially more than one mechanisms through which, high Pi reduces autophagy flux. High Pi decreases autophagosome formation through promoting beclin 1/BCL2 complex, and impairs autophagosome-lysosome function consequently blocking autophagosome and autolysosome recycling.…”

Section: High Phosphate Suppresses Autophagy Fluxmentioning

confidence: 99%

The tripartite interaction of phosphate, autophagy, and αKlotho in health maintenance

et al. 2020

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Aging-related organ degeneration is driven by multiple factors including the cell maintenance mechanisms of autophagy, the cytoprotective protein αKlotho, and the lesser known effects of excess phosphate (Pi), or phosphotoxicity. To examine the interplay between Pi, autophagy, and αKlotho, we used the BK/BK mouse (homozygous for mutant Becn1 F121A ) with increased autophagic flux, and αKlothohypomorphic mouse (kl/kl) with impaired urinary Pi excretion, low autophagy, and premature organ dysfunction. BK/BK mice live longer than WT littermates, and have heightened phosphaturia from downregulation of two key NaPi cotransporters in the kidney. The multi-organ failure in kl/kl mice was rescued in the double-mutant BK/ BK;kl/kl mice exhibiting lower plasma Pi, improved weight gain, restored plasma and renal αKlotho levels, decreased pathology of multiple organs, and improved fertility compared to kl/kl mice. The beneficial effects of heightened autophagy from Becn1 F121A was abolished by chronic high-Pi diet which also shortened life span in the BK/BK;kl/kl mice. Pi promoted beclin 1 binding to its negative regulator BCL2, which impairs autophagy flux. Pi downregulated αKlotho, which also independently impaired autophagy. In conclusion, Pi, αKlotho, and autophagy interact intricately 3130 | SHI et al.

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“…We show in the present study that these glucosylceramides are increased in the DRGs of Pink1SNCA mice strengthening the idea that they contribute to the pathology of sensory neurons. Mutations of GBA1, the key lysosomal enzyme catalyzing GlcCer degradation, have been associated with autophagolysosmal dysfunctions [66,67], increased alpha-synuclein toxicity [27,68] and disruptions of mitochondrial energy production [49]. GBA1 expression was unaltered in the DRGs of Pink1SNCA mice, and the ultrastructural morphology of lysosomes and lipid droplets in DRG neurons appeared to be normal for the age.…”

Section: Discussionmentioning

confidence: 99%

Early prodromal sensory neuropathy in Pink1-SNCA double mutant Parkinson mice

Valek¹,

Tran²,

Wilken-Schmitz³

et al. 2020

Preprint

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BACKGROUND: Parkinson's Disease (PD) is frequently associated with a prodromal sensory neuropathy, which manifests as sensory loss and eventually chronic pain. METHODS: The present study assessed somatosensory functions and the pathology of somatosensory neurons in Pink1-/-SNCAA53T double mutant mice (Pink1SNCA) who develop a PD-like disease > 15 months of age. RESULTS: Pink1SNCA mice showed the first manifestations of sensory dysfunctions at 6 months of age, which were characterized by a loss of thermal sensitivity but sparing of mechanical sensation, and decline of olfactory perception of pleasant odors. Mechanistically, the loss of thermal sensitivity was attributed to a strong reduction of transient receptor potential TRPV and TRPA channels at mRNA, protein and functional levels in the dorsal root ganglia (DRGs). Primary sensory neurons responded much less to stimulations with capsaicin, formalin or depolarization as assessed by calcium imaging. RNA sequencing pointed to additional deregulations of voltage dependent potassium channel subtypes, lowering of acidic fibroblast growth factor driven support, and alterations of sphingolipid metabolism. Analyses of sphingolipids of multiple classes revealed an accumulation of glucosylceramides mainly in the DRGs and loss of sphingosines and sphinganines in the sciatic nerve. Transmission electron microscopy of the DRGs revealed a higher frequency of neurons with swollen mitochondria, which was associated with a decrease of mitochondrial respiration in sensory ganglia, but not in the brain. CONCLUSION: The data support the view of a prodromal sensory disease in PD resulting from a combination of lipid allostasis and mitochondrial damage. Hence, Pink1SNCA mice phenocopy the PD-associated prodromal sensory neuropathy and reveal novel mechanistic insight.

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Cholesterol and multilamellar bodies: Lysosomal dysfunction in GBA-Parkinson disease

Cited by 59 publications

References 0 publications

Modeling Parkinson’s Disease With the Alpha-Synuclein Protein

Modeling Parkinson’s Disease With the Alpha-Synuclein Protein

The tripartite interaction of phosphate, autophagy, and αKlotho in health maintenance

Early prodromal sensory neuropathy in Pink1-SNCA double mutant Parkinson mice

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