Mini-review: Synaptojanin 1 and its implications in membrane trafficking

Choudhry, Hassaam; Aggarwal, Meha; Pan, Ping-Yue

doi:10.1016/j.neulet.2021.136288

Cited by 26 publications

(20 citation statements)

References 62 publications

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“…Mutations in SYNJ1 have been identified in an earlyonset autosomal recessive form of PD (PARK20) [45]. The pathomechanisms of PARK20 have been related to the dysfunction of synaptic vesicle recycling and the autophagy system [12,16,40]. However, the direct interplay between SYNJ1 and αSyn aggregation is not fully understood.…”

Section: Discussionmentioning

confidence: 99%

Phosphatidylinositol-3,4,5-trisphosphate interacts with alpha-synuclein and initiates its aggregation and formation of Parkinson’s disease-related fibril polymorphism

et al. 2023

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Lipid interaction with α-synuclein (αSyn) has been long implicated in the pathogenesis of Parkinson’s disease (PD). However, it has not been fully determined which lipids are involved in the initiation of αSyn aggregation in PD. Here exploiting genetic understanding associating the loss-of-function mutation in Synaptojanin 1 (SYNJ1), a phosphoinositide phosphatase, with familial PD and analysis of postmortem PD brains, we identified a novel lipid molecule involved in the toxic conversion of αSyn and its relation to PD. We first established a SYNJ1 knockout cell model and found SYNJ1 depletion increases the accumulation of pathological αSyn. Lipidomic analysis revealed SYNJ1 depletion elevates the level of its substrate phosphatidylinositol-3,4,5-trisphosphate (PIP3). We then employed Caenorhabditis elegans model to examine the effect of SYNJ1 defect on the neurotoxicity of αSyn. Mutations in SYNJ1 accelerated the accumulation of αSyn aggregation and induced locomotory defects in the nematodes. These results indicate that functional loss of SYNJ1 promotes the pathological aggregation of αSyn via the dysregulation of its substrate PIP3, leading to the aggravation of αSyn-mediated neurodegeneration. Treatment of cultured cell line and primary neurons with PIP3 itself or with PIP3 phosphatase inhibitor resulted in intracellular formation of αSyn inclusions. Indeed, in vitro protein–lipid overlay assay validated that phosphoinositides, especially PIP3, strongly interact with αSyn. Furthermore, the aggregation assay revealed that PIP3 not only accelerates the fibrillation of αSyn, but also induces the formation of fibrils sharing conformational and biochemical characteristics similar to the fibrils amplified from the brains of PD patients. Notably, the immunohistochemical and lipidomic analyses on postmortem brain of patients with sporadic PD showed increased PIP3 level and its colocalization with αSyn. Taken together, PIP3 dysregulation promotes the pathological aggregation of αSyn and increases the risk of developing PD, and PIP3 represents a potent target for intervention in PD.

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Section: Discussionmentioning

confidence: 99%

Phosphatidylinositol-3,4,5-trisphosphate interacts with alpha-synuclein and initiates its aggregation and formation of Parkinson’s disease-related fibril polymorphism

et al. 2023

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“…The reduced intracellular Ca 2+ signaling can in turn reduce the exocytotic release of glutamate from astrocytes that can further reduce Ca 2+ signaling leading to the negative feedback loop. 26 Accordingly, mitochondrial pathways responsible for glutamate metabolization (Got2 31 and Glud1 32 ) and regulators of intracellular vesicle recycling and secretion that contribute to glutamate release and homeostasis (Synj1, 33 Syt1 34 and Stx1 35 ) were found downregulated in astrocytes from 2-month-old Sorcs2 -/mice.…”

Section: Importance Of Sorcs2 In Neurovascular Couplingmentioning

confidence: 98%

SorCS2 modulates neurovascular coupling via glutamatergic and calcium signaling in astrocytes

Staehr

Postnov

et al. 2023

Preprint

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SorCS2 is involved in trafficking of membrane receptors and transporters. SorCS2 is implicated in brain disorders, but the mechanism remains uncertain. We hypothesized that SorCS2 expression is important for neurovascular coupling. Brains from P8 and 2-month-old wild type mice were stained for SorCS2 and compared to SorCS2 knockouts (Sorcs2-/-). Changes in cerebral perfusion in response to sensory stimulation, i.e., neurovascular coupling, were comparedin vivo. Neurovascular coupling was also assessed ex vivo in brain slices loaded with calcium-sensitive dye. Proteomics of astrocytes was analyzed for ingenuity pathways. SorCS2 was strongly expressed in astrocytic endfeet of P8 mice but only in few astrocytes from 2-month-old brains.Sorcs2-/-mice demonstrated reduced neurovascular coupling. This was associated with reduced astrocytic calcium response to neuronal excitation inSorcs2-/-mice. No difference in cerebral artery caliber nor in endothelial function was seen between wild type andSorcs2-/-mice. Proteomics indicated reduced glutamatergic signaling and suppressed calcium signaling inSorcs2-/-astrocytes. We suggest that SorCS2 expression is important for neurovascular coupling due to modulation of glutamatergic and calcium signaling in astrocytes.

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“…Synaptojanin-1 is a phosphoinositide phosphatase and importantly, mutations to the SYNJ1 gene, encoding synaptojanin-1, are associated with Parkinsonism (symptoms of bradykinesia and either rest tremor, rigidity or both) [ 82 , 83 , 84 ]. Synaptojanin-1 deficiency results in impaired endolysosomal sorting and trafficking of multiple receptors and transporters including AMPA, transferrin and GLUT-1 [ 85 ]. Synaptojanin-1-deficient astrocytes display reduced expression of the glucose transporter GLUT-1, suggesting that synaptojanin-1 may disrupt glucose-sensing pathways and may contribute to glucose starvation [ 86 ].…”

Section: Lrrk2 Mitochondrial Energy and Glucose/insulin Pathwaysmentioning

confidence: 99%

LRRK2 and Lipid Pathways: Implications for Parkinson’s Disease

2022

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Genetic alterations in the LRRK2 gene, encoding leucine-rich repeat kinase 2, are a common risk factor for Parkinson’s disease. How LRRK2 alterations lead to cell pathology is an area of ongoing investigation, however, multiple lines of evidence suggest a role for LRRK2 in lipid pathways. It is increasingly recognized that in addition to being energy reservoirs and structural entities, some lipids, including neural lipids, participate in signaling cascades. Early investigations revealed that LRRK2 localized to membranous and vesicular structures, suggesting an interaction of LRRK2 and lipids or lipid-associated proteins. LRRK2 substrates from the Rab GTPase family play a critical role in vesicle trafficking, lipid metabolism and lipid storage, all processes which rely on lipid dynamics. In addition, LRRK2 is associated with the phosphorylation and activity of enzymes that catabolize plasma membrane and lysosomal lipids. Furthermore, LRRK2 knockout studies have revealed that blood, brain and urine exhibit lipid level changes, including alterations to sterols, sphingolipids and phospholipids, respectively. In human LRRK2 mutation carriers, changes to sterols, sphingolipids, phospholipids, fatty acyls and glycerolipids are reported in multiple tissues. This review summarizes the evidence regarding associations between LRRK2 and lipids, and the functional consequences of LRRK2-associated lipid changes are discussed.

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Mini-review: Synaptojanin 1 and its implications in membrane trafficking

Cited by 26 publications

References 62 publications

Phosphatidylinositol-3,4,5-trisphosphate interacts with alpha-synuclein and initiates its aggregation and formation of Parkinson’s disease-related fibril polymorphism

Phosphatidylinositol-3,4,5-trisphosphate interacts with alpha-synuclein and initiates its aggregation and formation of Parkinson’s disease-related fibril polymorphism

SorCS2 modulates neurovascular coupling via glutamatergic and calcium signaling in astrocytes

LRRK2 and Lipid Pathways: Implications for Parkinson’s Disease

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