“… aSyn accumulation alters lipid droplet homeostasis. SLs and long-chain ceramides have been implicated in pro-inflammatory processes (reviewed in [ 3 , 14 , 19 , 80 , 118 , 134 ]), consistent with the growing role of neuroinflammation and immune response in PD. Fig.…”
Section: Discussionmentioning
confidence: 80%
“…This alteration in GCase localization leads to the accumulation of SLs, such as glucosylceramide and glucosylsphingosine [ 9 , 77 , 91 ]. Interestingly, some lipid species (sphingomyelin, ceramide and monohexosylceramides) have been found increased in the plasma of PD patients [ 77 ] and, importantly, their physiological role is not only structural but also of high importance for cellular processes like autophagy, senescence, and inflammation, among others [ 2 , 19 , 93 ]. In the proposed loss-of-function mechanism, the reduction in GCase enzymatic activity also affects the protein degradation systems through impairment in lysosomal function and recycling [ 123 , 153 ], which leads to impaired aSyn clearance and, consequently, to its accumulation [ 139 ].…”
Section: Gba1
Mutations and Sl Metabolism Alterations As A R...mentioning
The accumulation of proteinaceous inclusions in the brain is a common feature among neurodegenerative diseases such as Alzheimer’s disease, Parkinson’s disease (PD), and dementia with Lewy bodies (DLB). The main neuropathological hallmark of PD and DLB are inclusions, known as Lewy bodies (LBs), enriched not only in α-synuclein (aSyn), but also in lipid species, organelles, membranes, and even nucleic acids. Furthermore, several genetic risk factors for PD are mutations in genes involved in lipid metabolism, such as GBA1, VSP35, or PINK1. Thus, it is not surprising that mechanisms that have been implicated in PD, such as inflammation, altered intracellular and vesicular trafficking, mitochondrial dysfunction, and alterations in the protein degradation systems, may be also directly or indirectly connected through lipid homeostasis. In this review, we highlight and discuss the recent evidence that suggests lipid biology as important drivers of PD, and which require renovated attention by neuropathologists. Particularly, we address the implication of lipids in aSyn accumulation and in the spreading of aSyn pathology, in mitochondrial dysfunction, and in ER stress. Together, this suggests we should broaden the view of PD not only as a proteinopathy but also as a lipidopathy.
“… aSyn accumulation alters lipid droplet homeostasis. SLs and long-chain ceramides have been implicated in pro-inflammatory processes (reviewed in [ 3 , 14 , 19 , 80 , 118 , 134 ]), consistent with the growing role of neuroinflammation and immune response in PD. Fig.…”
Section: Discussionmentioning
confidence: 80%
“…This alteration in GCase localization leads to the accumulation of SLs, such as glucosylceramide and glucosylsphingosine [ 9 , 77 , 91 ]. Interestingly, some lipid species (sphingomyelin, ceramide and monohexosylceramides) have been found increased in the plasma of PD patients [ 77 ] and, importantly, their physiological role is not only structural but also of high importance for cellular processes like autophagy, senescence, and inflammation, among others [ 2 , 19 , 93 ]. In the proposed loss-of-function mechanism, the reduction in GCase enzymatic activity also affects the protein degradation systems through impairment in lysosomal function and recycling [ 123 , 153 ], which leads to impaired aSyn clearance and, consequently, to its accumulation [ 139 ].…”
Section: Gba1
Mutations and Sl Metabolism Alterations As A R...mentioning
The accumulation of proteinaceous inclusions in the brain is a common feature among neurodegenerative diseases such as Alzheimer’s disease, Parkinson’s disease (PD), and dementia with Lewy bodies (DLB). The main neuropathological hallmark of PD and DLB are inclusions, known as Lewy bodies (LBs), enriched not only in α-synuclein (aSyn), but also in lipid species, organelles, membranes, and even nucleic acids. Furthermore, several genetic risk factors for PD are mutations in genes involved in lipid metabolism, such as GBA1, VSP35, or PINK1. Thus, it is not surprising that mechanisms that have been implicated in PD, such as inflammation, altered intracellular and vesicular trafficking, mitochondrial dysfunction, and alterations in the protein degradation systems, may be also directly or indirectly connected through lipid homeostasis. In this review, we highlight and discuss the recent evidence that suggests lipid biology as important drivers of PD, and which require renovated attention by neuropathologists. Particularly, we address the implication of lipids in aSyn accumulation and in the spreading of aSyn pathology, in mitochondrial dysfunction, and in ER stress. Together, this suggests we should broaden the view of PD not only as a proteinopathy but also as a lipidopathy.
“…Pathological changes in cells caused by expression of the defective GCase enzyme lead to disruption of the protein processing system and oxidative stress [ 27 ]. The study of the processes of oxidative stress and endoplasmic reticulum stress in cells is possible by means of genetically encoded biosensors [ 28 ].…”
Section: Discussionmentioning
confidence: 99%
“…It has been shown that astrocytes not only suffer from the effects of neurotoxic α-synuclein but also participate in its distribution in the brain [25]. Research has demonstrated that lysosomal dysfunction in astrocytes results in the accumulation of α-synuclein and contributes to astrocyte-induced inflammation [26] Pathological changes in cells caused by expression of the defective GCase enzyme lead to disruption of the protein processing system and oxidative stress [27]. The study of the processes of oxidative stress and endoplasmic reticulum stress in cells is possible by means of genetically encoded biosensors [28].…”
Parkinson’s disease (PD) is a neurodegenerative disorder that ranks second in prevalence after Alzheimer’s disease. The number of PD diagnoses increases annually. Nevertheless, modern PD treatments merely mitigate symptoms rather than preventing neurodegeneration progression. The creation of an appropriate model to thoroughly study the mechanisms of PD pathogenesis remains a current challenge in biomedicine. Recently, there has been an increase in data regarding the involvement of not only dopaminergic neurons of the substantia nigra but also astrocytes in the pathogenesis of PD. Cell models based on induced pluripotent stem cells (iPSCs) and their differentiated derivatives are a useful tool for studying the contribution and interaction of these two cell types in PD. Here, we generated two iPSC lines, ICGi034-B and ICGi034-C, by reprogramming peripheral blood mononuclear cells of a patient with a heterozygous mutation c.1226A>G (p.N370S) in the GBA1 gene by non-integrating episomal vectors encoding OCT4, KLF4, L-MYC, SOX2, LIN28, and mp53DD. The iPSC lines demonstrate the expression of pluripotency markers and are capable of differentiating into three germ layers. We differentiated the ICGi034-B and ICGi034-C iPSC lines into astrocytes. This resulting cell model can be used to study the involvement of astrocytes in the pathogenesis of GBA-associated PD.
“…An abundance of protein aggregates such as Lewy bodies and loss of dopaminergic neurons within the substantia nigra bring about the classic symptoms of PD. 1 Symptoms include resting tremor, bradykinesia, muscular rigidity, postural gait impairment, olfactory dysfunction, cognitive impairment, psychiatric symptoms, sleep disorders, autonomic dysfunction, pain, and fatigue. 2 Treatment options for PD include both medical and surgical approaches.…”
BACKGROUND
Treatment options for Parkinson’s disease (PD) include both medical and surgical approaches. Deep brain stimulation (DBS) is a surgical procedure that aims to improve motor symptomatology.
OBSERVATIONS
A 66-year-old White male with a 9-year history of PD presented to the neurosurgery clinic for DBS consideration. On the morning of scheduled surgery, preoperative laboratory test results revealed a prolonged prothrombin time of 50 seconds. Surgery was postponed, and further work-up revealed that the patient had a positive test result for lupus anticoagulant (LA). DBS implantation was performed 2 months later. The first stage of surgery was uneventful. The patient returned 1 week later for the second stage. Postoperatively, the patient exhibited a diminished level of consciousness. Computed tomography revealed left frontal intraparenchymal hemorrhage with surrounding edema, trace subarachnoid hemorrhage, intraventricular hemorrhage, and midline shift.
LESSONS
The authors suspect that the hemorrhage occurred secondary to venous infarct, because LA is associated with a paradoxically increased risk of thrombosis. Although there is no documented association between LA and acute or delayed hemorrhage, this case demonstrates a possible relationship in a patient following DBS placement. More research is needed to confirm an association with coexisting LA with PD and an increased hemorrhage risk in neurosurgical interventions.
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