Processing and maturation of human glucocerebrosidase

Bendikov-Bar, Inna; Maor, Gali; Horowitz, Mia

doi:10.2217/ebo.12.298

Cited by 1 publication

(1 citation statement)

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“…A number of inhibitory small molecule chaperone candidates have been identified as potential treatments for GBA-PD, including repurposed drugs such as ambroxol and isofagomine [39,221]. In fibroblasts and neurons with GBA mutations, such chaperones have demonstrated efficacy in increasing the GCase protein level and activity and aided in the trafficking of mutant GCase to the lysosome [39,90,138,213,218,221,222,230]. Both ambroxol and isofagomine have been shown to successfully reduce ER stress and improve symptoms in GBA-mutant Drosophila flies [90,217,223].…”

Section: Gcase As a Therapeutic Targetmentioning

confidence: 99%

GBA Variants and Parkinson Disease: Mechanisms and Treatments

Smith

Schapira

2022

Cells

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The GBA gene encodes for the lysosomal enzyme glucocerebrosidase (GCase), which maintains glycosphingolipid homeostasis. Approximately 5–15% of PD patients have mutations in the GBA gene, making it numerically the most important genetic risk factor for Parkinson disease (PD). Clinically, GBA-associated PD is identical to sporadic PD, aside from the earlier age at onset (AAO), more frequent cognitive impairment and more rapid progression. Mutations in GBA can be associated with loss- and gain-of-function mechanisms. A key hallmark of PD is the presence of intraneuronal proteinaceous inclusions named Lewy bodies, which are made up primarily of alpha-synuclein. Mutations in the GBA gene may lead to loss of GCase activity and lysosomal dysfunction, which may impair alpha-synuclein metabolism. Models of GCase deficiency demonstrate dysfunction of the autophagic-lysosomal pathway and subsequent accumulation of alpha-synuclein. This dysfunction can also lead to aberrant lipid metabolism, including the accumulation of glycosphingolipids, glucosylceramide and glucosylsphingosine. Certain mutations cause GCase to be misfolded and retained in the endoplasmic reticulum (ER), activating stress responses including the unfolded protein response (UPR), which may contribute to neurodegeneration. In addition to these mechanisms, a GCase deficiency has also been associated with mitochondrial dysfunction and neuroinflammation, which have been implicated in the pathogenesis of PD. This review discusses the pathways associated with GBA-PD and highlights potential treatments which may act to target GCase and prevent neurodegeneration.

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