GBA, Gaucher Disease, and Parkinson’s Disease: From Genetic to Clinic to New Therapeutic Approaches

Abstract

Parkinson’s disease (PD) is the second most common degenerative disorder. Although the disease was described more than 200 years ago, its pathogenetic mechanisms have not yet been fully described. In recent years, the discovery of the association between mutations of the GBA gene (encoding for the lysosomal enzyme glucocerebrosidase) and PD facilitated a better understating of this disorder. GBA mutations are the most common genetic risk factor of the disease. However, mutations of this gene can be found in different phenotypes, such as Gaucher’s disease (GD), PD, dementia with Lewy bodies (DLB) and rapid eye movements (REM) sleep behavior disorders (RBDs). Understanding the pathogenic role of this mutation and its different manifestations is crucial for geneticists and scientists to guide their research and to select proper cohorts of patients. Moreover, knowing the implications of the GBA mutation in the context of PD and the other associated phenotypes is also important for clinicians to properly counsel their patients and to implement their care. With the present review we aim to describe the genetic, clinical, and therapeutic features related to the mutation of the GBA gene.

Nanopore sequencing of the glucocerebrosidase (GBA) gene in a New Zealand Parkinson's disease cohort

“…Interestingly, p.N409S, p.E365K and p.T408 M are all frequently overrepresented in patients with REM-sleep behavior disorder (RBD). Patients with RBD have a significantly elevated risk of developing PD with dementia [3,27,28].…”

“…GCase is an enzyme involved in glycolipid metabolism, and mutations in GBA lead to a marked decrease in GCase activity [2]. Bi-allelic mutations in GBA result in excessive accumulation of the GCase substrate, GlcCer in macrophages, causing the rare lysosomal storage disorder, Gaucher disease (GD) [3,4]. Heterozygous GBA mutations were initially believed to be benign; however, Parkinsonism was frequently reported in GD patients and their non-GD family members [5].…”

“…Heterozygous GBA mutations were initially believed to be benign; however, Parkinsonism was frequently reported in GD patients and their non-GD family members [5]. It is now clear that individuals with these GBA mutations associated with GD in the heterozygous state have a substantially elevated risk of developing PD compared with non-carriers [3,6]. Furthermore, PD patients with GBA mutations have a noticeably earlier age of PD onset and a slightly increased risk of cognitive effects such as dementia, as well as a higher incidence of psychosis and delirium [7,8].…”

Hyperferritinemia and diagnosis of type 1 Gaucher disease

“…Such classification is based on the presence of central nervous system involvement, being type 1 the “non‐neuronopathic”, type 2 the “acute neuronopathic”, and type 3 the “chronic neuronopathic” form of the disease . A certain degree of overlap is possible, particularly regarding the occurrence of Parkinsonism in GD1 patients . Gaucher Disease type 1 accounts for about 90% of all GD cases, and has a heterogeneous clinical expression, ranging from overt visceral and bone involvement in childhood/early‐adulthood to more faded manifestations in late‐adulthood.…”

Pre-clinical Mouse Models of Neurodegenerative Lysosomal Storage Diseases

“…Unfortunately, there is no effective treatment for the neurologic damage of GD types 2 and 3. HSCT can reverse the non-neurological effects of the disease, but the procedure carries a high risk and is rarely performed in individuals with Gaucher disease (Riboldi and Fonzo, 2019). Interestingly, patients with type 1 are at increased risk for Parkinson's disease and Lewy Body Dementia.…”