Neuropathological Features of Gaucher Disease and Gaucher Disease with Parkinsonism

Abstract

Deficient acid β-glucocerebrosidase activity due to biallelic mutations in GBA1 results in Gaucher disease (GD). Patients with this lysosomal storage disorder exhibit a wide range of associated manifestations, spanning from virtually asymptomatic adults to infants with severe neurodegeneration. While type 1 GD (GD1) is considered non-neuronopathic, a small subset of patients develop parkinsonian features. Variants in GBA1 are also an important risk factor for several common Lewy body disorders (LBDs). Neuropathological examinations of patients with GD, including those who developed LBDs, are rare. GD primarily affects macrophages, and perivascular infiltration of Gaucher macrophages is the most common neuropathologic finding. However, the frequency of these clusters and the affected anatomical region varies. GD affects astrocytes, and, in neuronopathic GD, neurons in cerebral cortical layers 3 and 5, layer 4b of the calcarine cortex, and hippocampal regions CA2–4. In addition, several reports describe selective degeneration of the cerebellar dentate nucleus in chronic neuronopathic GD. GD1 is characterized by astrogliosis without prominent neuronal loss. In GD-LBD, widespread Lewy body pathology is seen, often involving hippocampal regions CA2–4. Additional neuropathological examinations in GD are sorely needed to clarify disease-specific patterns and elucidate causative mechanisms relevant to GD, and potentially to more common neurodegenerative diseases.

More than meets the eye in Parkinson’s disease and other synucleinopathies: from proteinopathy to lipidopathy

“…Gaucher’s Disease patients can be classified into five types (1, 2, 3, perinatal lethal, and cardiovascular) according to substrate accumulation and neuronal affections. Type 2 and 3 patients show a degree of neurodegeneration and neuropathic manifestations that resemble clinical features of PD (reviewed in [ 66 ]). Initially, this suggested that GCase deficiency degree could be an important mechanism involved in PD.…”

Pathways to healing: Plants with therapeutic potential for neurodegenerative diseases

“…Gaucher disease is an LSD resulting from a lysosomal defect in β-glucocerebrosidase (GCase), the enzyme responsible for the degradation of GC, leading to GC accumulation, (reviewed by Aerts et al, 2019 ). In some of the disease phenotypes this leads to neuropathological effects such as dysfunctional astrocyte activation and neuronal loss (reviewed by Furderer et al, 2022 ). One treatment strategy aims to use pharmacological chaperones (PCs) to promote correct folding of mutated enzymes and their trafficking to lysosomes, enabling trafficking of the enzyme to lysosomes and restoration of enzyme function ( Parenti, 2009 ).…”

A review on Gaucher disease: therapeutic potential of β-glucocerebrosidase-targeted mRNA/saRNA approach

“…In specific circumstances, the distinctions between the three forms of GD may become unclear. Although GD1 is clinically non-neuronopathic, in some cases, patients develop neurological symptoms 66 . Besides, some patients exhibit an intermediate phenotype that falls between GD2 and GD3 with a survival range of 3 to 8 years 67 .…”