Parkinson's disease (PD) is a progressive neurological disorder estimated to affect 7-10 million people worldwide. There is no treatment available that cures or slows the progression of PD. Elevated leucine-rich repeat kinase 2 (LRRK2) activity has been associated with genetic and sporadic forms of PD and, thus, reducing LRRK2 function is a promising therapeutic strategy.
View Article and Find Full Text PDFThe Parkinson disease (PD) genetic LRRK2 gain-of-function mutations may relate to the ER pathological changes seen in PD patients at postmortem. Human induced pluripotent stem cell (iPSC)-derived neurons with the PD pathogenic LRRK2 G2019S mutation exhibited neurite collapse when challenged with the ER Ca influx sarco/ER Ca-ATPase inhibitor thapsigargin (THP). Baseline ER Ca levels measured with the ER Ca indicator CEPIA-ER were lower in LRRK2 G2019S human neurons, including in differentiated midbrain dopamine neurons in vitro.
View Article and Find Full Text PDFThis report demonstrates insoluble alpha-synuclein (aSYN)+ aggregates in human sporadic Parkinson's disease (PD) midbrain that are linearly correlated with loss of glucocerebrosidase (GCase) activity. To identify early protein-lipid interactions that coincide with loss of lipid homeostasis, an aging study was carried out in mice with age-dependent reductions in GCase function. The analysis identified aberrant lipid-association by aSYN and hyperphosphorylated Tau (pTau) in a specific subset of neurotransmitter-containing, Secretogranin II (SgII)+ large, dense-core vesicles (LDCVs) responsible for neurotransmission of dopamine and other monoamines.
View Article and Find Full Text PDFGPNMB is a glycoprotein observed upon tissue damage and inflammation and is associated with astrocytes, microglia, and macrophages. Gene variations in GPNMB are linked with Parkinson's disease (PD) risk, and changes in protein levels of GPNMB have been found in lysosomal storage disorders, including Gaucher's disease with glucocerebrosidase (GCase) deficiency. In the current study, GPNMB increases were seen in the substantia nigra (SN) of PD patients compared to age-matched controls.
View Article and Find Full Text PDF