Pathological α-syn aggregation is mediated by glycosphingolipid chain length and the physiological state of α-syn in vivo

Fredriksen, Kristina; Aivazidis, Stefanos; Sharma, Karan; Burbidge, Kevin; Pitcairn, Caleb; Zunke, Friederike; Gelyana, Eilrayna; Mazzulli, Joseph R.

doi:10.1073/pnas.2108489118

Cited by 26 publications

(14 citation statements)

References 58 publications

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“…Moreover, when examining the various chain lengths for GlcCer, GlcCer18:0 was the most common isoform in the mice. A recent study showed that longer carbon lipid chains (>C22) lead to more pathologic outcomes (Fredriksen et al, 2021), and thus GlcCer18:0 in the mouse brain may not be impacted in this PD model. Overall, accumulating evidence points to aberrations in metabolism of GlcSph, and not GlcCer, as playing a pathologic role.…”

Section: Discussionmentioning

confidence: 91%

Neuronopathic GBA1 L444P mutation accelerates Glucosylsphingosine levels and formation of hippocampal alpha-synuclein inclusions

Mahoney-Crane

Viswanathan

Russell

et al. 2022

Preprint

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The most common genetic risk factor for Parkinson disease (PD) is heterozygous mutations in the GBA1 gene which encodes for the lysosomal enzyme, glucocerebrosidase (GCase). GCase impairments are associated with an accumulation of abnormal α-synuclein (α-syn) called Lewy pathology, which characterizes PD. PD patients heterozygous for the GBA1 L444P mutation (GBA1+/L444P) have a 5.6-fold increased risk of cognitive impairments. In this study, we used GBA1+/L444P mice to determine the effects of this severe GBA1 mutation on lipid metabolism, expression of synaptic proteins, behavior, and α-syn inclusion formation. GBA1+/L444P mice showed reduced GCase activity in limbic brain regions and expressed lower levels of hippocampal vGLUT1 compared to wildtype (GBA1+/+) mice. GBA+/L444P mice also demonstrated impaired fear conditioning, but no motor deficits. We show, using mass spectrometry, that mutant GCase and age increased levels of glucosylsphingosine (GlcSph), but not glucosylceramide (GlcCer), in the brains and serum of GBA1+/L444P mice. Aged GBA1+/+ mice also showed increased levels of GlcSph, and decreased GlcCer. To model disease pathology, templated α-syn pathology was used. α-Syn inclusions were increased in the hippocampus of GBA1+/L444P mice compared to GBA1+/+ mice, but not in the cortex, or substantia nigra pars compacta (SNc). Pathologic α-syn did not cause a loss of dopamine neurons in the SNc. Treatment with a GlcCer synthase inhibitor prevented loss of cortical α-syn inclusions, but not loss of dopamine neurons. Overall, these data suggest the critical importance to evaluate the contribution of hippocampal pathologic α-syn and brain and serum glucosylsphingosine in synucleinopathies.

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Section: Discussionmentioning

confidence: 91%

Neuronopathic GBA1 L444P mutation accelerates Glucosylsphingosine levels and formation of hippocampal alpha-synuclein inclusions

Mahoney-Crane

Viswanathan

Russell

et al. 2022

Preprint

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“…Various GSL chain length isomers may play different roles in GBA-PD progression but this is not yet fully elucidated. 26,27 The absolute quantity of the different isoforms of a specific GSL also differs widely within a cell type (Figure 12 in Data S1). In multiple previous studies 19,28 all GSL chain lengths are totaled, meaning the signal of sparse isoforms will be overshadowed by those that are more abundant.…”

Section: Discussionmentioning

confidence: 99%

“…Various GSL chain length isomers may play different roles in GBA‐PD progression but this is not yet fully elucidated 26,27 . The absolute quantity of the different isoforms of a specific GSL also differs widely within a cell type (Figure 12 in Data S1).…”

Section: Discussionmentioning

confidence: 99%

A Biomarker Study in Patients with GBA1‐Parkinson's Disease and Healthy Controls

et al. 2023

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A BS TRACT: Background: Molecules related to glucocerebrosidase (GCase) are potential biomarkers for development of compounds targeting GBA1-associated Parkinson's disease (GBA-PD). Objectives: Assessing variability of various glycosphingolipids (GSLs) in plasma, peripheral blood mononuclear cells (PBMCs), and cerebrospinal fluid (CSF) across GBA-PD, idiopathic PD (iPD), and healthy volunteers (HVs). Methods: Data from five studies were combined. Variability was assessed of glucosylceramide (various isoforms), lactosylceramide (various isoforms), glucosylsphingosine, galactosylsphingosine, GCase activity (using fluorescent 4-methylumbeliferryl-β-glucoside), and GCase protein (using enzyme-linked immunosorbent assay) in plasma, PBMCs, and CSF if available, in GBA-PD, iPD, and HVs. GSLs in leukocyte subtypes were compared in HVs. Principal component analysis was used to explore global patterns in GSLs, clinical characteristics (Movement Disorder Society -Unified Parkinson's Disease Rating Scale Part 3 [MDS-UPDRS-3], Mini-Mental State Examination [MMSE], GBA1 mutation type), and participant status (GBA-PD, iPD, HVs). Results: Within-subject between-day variability ranged from 5.8% to 44.5% and was generally lower in plasma than in PBMCs. Extracellular glucosylceramide levels (plasma) were slightly higher in GBA-PD compared with both iPD and HVs, while intracellular levels were comparable. GSLs in the different matrices (plasma, PBMCs, CSF) did not correlate. Both lactosylceramide and glucosylsphingosine were more abundant in granulocytes compared with monocytes and lymphocytes. Absolute levels of GSL isoforms differed greatly. GBA1 mutation types could not be differentiated based on GSL data. Conclusions: Glucosylceramide can stably be measured over days in both plasma and PBMCs and may be used as a biomarker in clinical trials targeting GBA-PD. Glucosylsphingosine and lactosylceramide are stable in plasma but are strongly affected by leukocyte subtypes in PBMCs. GBA-PD could be differentiated from iPD and HVs, primarily based on glucosylceramide levels in plasma.

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“…However, two independent studies carried out in mice carrying the homozygous GBA D409V mutation observed no inflammatory response, even in the presence of typical signs of α-syn pathology [ 116 , 117 ]. In contrast, specific inhibition of GCase in mice resulted in α-syn neuropathology and inflammation, as revealed by elevated GFAP levels that are indicative of astrogliosis [ 118 ].…”

Section: Inflammation In Pdmentioning

confidence: 99%

Neurodegeneration and Neuroinflammation in Parkinson’s Disease: a Self-Sustained Loop

Arena

Sharma

Agyeah

et al. 2022

Curr Neurol Neurosci Rep

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Purpose of Review Neuroinflammation plays a significant role in Parkinson’s disease (PD) etiology along with mitochondrial dysfunction and impaired proteostasis. In this context, mechanisms related to immune response can act as modifiers at different steps of the neurodegenerative process and justify the growing interest in anti-inflammatory agents as potential disease-modifying treatments in PD. The discovery of inherited gene mutations in PD has allowed researchers to develop cellular and animal models to study the mechanisms of the underlying biology, but the original cause of neuroinflammation in PD is still debated to date. Recent Findings Cell autonomous alterations in neuronal cells, including mitochondrial damage and protein aggregation, could play a role, but recent findings also highlighted the importance of intercellular communication at both local and systemic level. This has given rise to debate about the role of non-neuronal cells in PD and reignited intense research into the gut-brain axis and other non-neuronal interactions in the development of the disease. Whatever the original trigger of neuroinflammation in PD, what appears quite clear is that the aberrant activation of glial cells and other components of the immune system creates a vicious circle in which neurodegeneration and neuroinflammation nourish each other. Summary In this review, we will provide an up-to-date summary of the main cellular alterations underlying neuroinflammation in PD, including those induced by environmental factors (e.g. the gut microbiome) and those related to the genetic background of affected patients. Starting from the lesson provided by familial forms of PD, we will discuss pathophysiological mechanisms linked to inflammation that could also play a role in idiopathic forms. Finally, we will comment on the potential clinical translatability of immunobiomarkers identified in PD patient cohorts and provide an update on current therapeutic strategies aimed at overcoming or preventing inflammation in PD.

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Pathological α-syn aggregation is mediated by glycosphingolipid chain length and the physiological state of α-syn in vivo

Cited by 26 publications

References 58 publications

Neuronopathic GBA1 L444P mutation accelerates Glucosylsphingosine levels and formation of hippocampal alpha-synuclein inclusions

Neuronopathic GBA1 L444P mutation accelerates Glucosylsphingosine levels and formation of hippocampal alpha-synuclein inclusions

A Biomarker Study in Patients with GBA1‐Parkinson's Disease and Healthy Controls

Neurodegeneration and Neuroinflammation in Parkinson’s Disease: a Self-Sustained Loop

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