The Complicated Relationship between Gaucher Disease and Parkinsonism: Insights from a Rare Disease

Abstract

The discovery of a link between mutations in GBA1, encoding the lysosomal enzyme glucocerebrosidase, and the synucleinopathies directly resulted from the clinical recognition of patients with Gaucher disease with parkinsonism. Mutations in GBA1 are now the most common known genetic risk factor for several Lewy body disorders, and an inverse relationship exists between levels of glucocerebrosidase and oligomeric α-synuclein. While the underlying mechanisms are still debated, this complicated association is shedding light on the role of lysosomes in neurodegenerative disorders, demonstrating how insights from a rare disorder can direct research into the pathogenesis and therapy of seemingly unrelated common diseases.

The Spectrum of Movement Disorders in Childhood‐onset Lysosomal Storage Diseases

“…With exciting new genetic and clinical links between LSD and adult‐onset neurodegenerative diseases such as sporadic Parkinson's disease, it is imperative to systematically define the spectrum of movement disorders in childhood‐onset LSD. Here we systematically investigated the presence of movement disorders in a large cohort of children with genetically or biochemically confirmed LSD.…”

Glucocerebrosidase haploinsufficiency in A53T α-synuclein mice impacts disease onset and course

“…Identifying the mechanistic basis for the association between GBA1 and the synucleinopathies continues to be a challenge, and additional pathways, genes and/or epigenetics may play a role [9,32]. An appropriate animal model would greatly facilitate our understanding of this complicated relationship.…”

Lysosomes as a therapeutic target

“…Approximately 15% of patients with PD have a family history of the disorder, although the underlying molec ular mechanisms remain unclear. In the context of lysosomal dysfunction, it is notable that the most com mon of the known PD genetic mutations are in GBA1 (encoding the lysosomal β GCAse) -the same gene that underlies Gaucher disease -which are present in up to 10% of patients with PD in the United States 167 . GBA1 mutations are also associated with dementia with Lewy bodies 167 .…”