Cell type-specific lipid storage changes in Parkinson’s disease patient brains are recapitulated by experimental glycolipid disturbance

Abstract

Neurons are dependent on proper trafficking of lipids to neighboring glia for lipid exchange and disposal of potentially lipotoxic metabolites, producing distinct lipid distribution profiles among various cell types of the central nervous system. Little is known of the cellular distribution of neutral lipids in the substantia nigra (SN) of Parkinson’s disease (PD) patients and its relationship to inflammatory signaling. This study aimed to determine human PD SN neutral lipid content and distribution in dopaminergic neurons, astrocytes, and microglia relative to age-matched healthy subject controls. The results show that while total neutral lipid content was unchanged relative to age-matched controls, the levels of whole SN triglycerides were correlated with inflammation-attenuating glycoprotein non-metastatic melanoma protein B (GPNMB) signaling in human PD SN. Histological localization of neutral lipids using a fluorescent probe (BODIPY) revealed that dopaminergic neurons and midbrain microglia significantly accumulated intracellular lipids in PD SN, while adjacent astrocytes had a reduced lipid load overall. This pattern was recapitulated by experimental in vivo inhibition of glucocerebrosidase activity in mice. Agents or therapies that restore lipid homeostasis among neurons, astrocytes, and microglia could potentially correct PD pathogenesis and disease progression.

Wild-type GBA1 increases the α-synuclein tetramer–monomer ratio, reduces lipid-rich aggregates, and attenuates motor and cognitive deficits in mice

“…Hence, it is likely that certain alterations in the neuronal lipid composition can promote PD pathogenesis by acting on lysosomal lipid clearance pathways. This concept fits with the growing evidence that lipid dyshomeostasis is an imprint factor in hu PD ( 7 , 53 – 55 ), as has been observed in PD-relevant neuronal cultures ( 19 , 56 – 58 ) and mouse models ( 22 , 59 , 60 ). Therefore, a likely mechanistic explanation for the therapeutic benefits of GBA expression seen here is a shift in FA balance that contributes to proper, amphipathic α-helix in αS that stabilizes tetramer formation, perhaps by enhancing the transient interaction of αS monomers with highly curved vesicle membranes.…”

Proteomics and bioinformatics reveal insights into neuroinflammation in the acute to subacute phases in rat models of spinal cord contusion injury

“…These alterations could be attributed to the formation of foamy macrophages after SCI 32,33 . There is a growing body of evidence that shows that cellular lipid accumulation is associated with neuroinflammation and plays a critical role in the pathogenesis of neurodegeneration 18,34 . For instance, cholesterol accumulation induced lysosomal rupture and inflammasome activation in a demyelination model in aged mice as a result of excessive phagocytosis of myelin debris 35 .…”

Lipid Droplets in the Pathogenesis of Hereditary Spastic Paraplegia

“…Notably, most studies describing LD dysfunction in neurodegeneration, report LD accumulation as a detrimental effect ( Brekk et al, 2020 ; Marschallinger et al, 2020 ). Is an increased LD number just a read-out of inefficient FA catabolism or are LDs toxic for neurons?…”