A number of genetic risk factors have been identified over the past decade for Parkinson’s Disease (PD), with variants in GBA prominent among them. GBA encodes the lysosomal enzyme that degrades the glycosphingolipid, glucosylceramide (GlcCer), with the activity of this enzyme defective in Gaucher disease. Based on the ill-defined relationship between glycosphingolipid metabolism and PD, we now analyze levels of various lipids by liquid chromatography/electrospray ionization-tandem mass spectrometry in four brain regions from age- and sex-matched patient samples, including idiopathic PD, PD patients with a GBA mutation and compare both to control brains (n = 21 for each group) obtained from individuals who died from a cause unrelated to PD. Of all the glycerolipids, sterols, and (glyco)sphingolipids (251 lipids in total), the only lipid class which showed significant differences were the gangliosides (sialic acid-containing complex glycosphingolipids), which were elevated in 3 of the 4 PD-GBA brain regions. There was no clear correlation between levels of individual gangliosides and the genetic variant in Gaucher disease [9 samples of severe (neuronopathic), 4 samples of mild (non-neuronopathic) GBA variants, and 8 samples with low pathogenicity variants which have a higher risk for development of PD]. Most brain regions, i.e. occipital cortex, cingulate gyrus, and striatum, did not show a statistically significant elevation of GlcCer in PD-GBA. Only one region, the middle temporal gyrus, showed a small, but significant elevation in GlcCer concentration in PD-GBA. We conclude that changes in ganglioside, but not in GlcCer levels, may contribute to the association between PD and GBA mutations.

Most lysosomal storage diseases (LSDs) have a significant neurological component, including types 2 and 3 Gaucher disease (neuronal forms of Gaucher disease; nGD). No therapies are currently available for nGD since the recombinant enzymes used in the systemic form of Gaucher disease do not cross the blood–brain barrier (BBB). However, a number of promising approaches are currently being tested, including substrate reduction therapy (SRT), in which partial inhibition of the synthesis of the glycosphingolipids (GSLs) that accumulate in nGD lowers their accumulation. We now induce nGD in mice by injection with conduritol B‐epoxide (CBE), an irreversible inhibitor of acid beta‐glucosidase (GCase), the enzyme defective in nGD, with or without co‐injection with Genz‐667161, a prototype for SRT which crosses the BBB. Significant neuropathology, and a reduction in lifespan, was observed upon CBE injection, and this was largely reversed by co‐injection with Genz‐667161, along with a reduction in glucosylceramide and glucosylsphingosine levels. Analysis of gene expression by RNAseq revealed that Genz‐667161 largely reversed the changes in genes and pathways that were differentially expressed upon CBE injection, specifically pathways of GSL metabolism, lipoproteins and other lipid metabolic pathways, lipid droplets, astrocyte activation, neuronal function, and to some extent, neuroinflammation. Together, this demonstrates the efficacy of SRT to reverse the effects of substrate accumulation on pathological components and pathways in nGD brain.

The lysosome is a central player in the cell, acting as a clearing house for macromolecular degradation, but also plays a critical role in a variety of additional metabolic and regulatory processes. The lysosome has recently attracted the attention of neurobiologists and neurologists since a number of neurological diseases involve a lysosomal component. Among these is Parkinson’s disease (PD). While heterozygous and homozygous mutations in GBA1 are the highest genetic risk factor for PD, studies performed over the past decade have suggested that lysosomal loss of function is likely involved in PD pathology, since a significant percent of PD patients have a mutation in one or more genes that cause a lysosomal storage disease (LSD). Although the mechanistic connection between the lysosome and PD remains somewhat enigmatic, significant evidence is accumulating that lysosomal dysfunction plays a central role in PD pathophysiology. Thus, lysosomal dysfunction, resulting from mutations in lysosomal genes, may enhance the accumulation of α-synuclein in the brain, which may result in the earlier development of PD.

Homozygous mutations in GBA1 cause the most common lysosomal storage disease (LSD), namely, Gaucher disease (GD). Mutations (homozygous or heterozygous) in GBA1 are also the highest genetic risk factor for Parkinson's disease (PD), 1 although the mechanistic basis for this relationship is not known. We now suggest, based on well-documented data in some cases and on more anecdotal data in others, that there is a resemblance in some nonmotor symptoms (NMSs) between PD and LSDs. This may indicate that brain regions associated with NMSs are more vulnerable to changes in lysosomal activity and α-synuclein deposition as a result of lysosomal dysfunction. NMSs in PD patients with an LSD mutation have been mainly examined clinically in individuals heterozygous for GBA1 mutations rather than in mutations for other genes that cause an LSD, as the latter have only been recently identified as risk factors for PD. 2 It is important to distinguish between LSD carriers and patients in terms of PD-related NMSs because LSD carriers do not display overt LSD symptoms, although LSD carriers do affect susceptibility toward the development of neurological diseases such as PD. 1 Indeed, a recent study on Niemann-Pick (NPC1) carriers suggested heterozygosity is a high risk factor for late-onset neurodegeneration. 3 The significant overlap in NMSs between PD and LSDs (documented with appropriate references in Table 1) suggests that NMSs may be the cause of at least 1 common trait between these apparently disparate diseases. LSDs are rare, and patients often succumb at a young age. Nevertheless, reports of NMSs in late-onset or chronic forms of LSDs suggest a similarity between the presentation of NMSs in LSDs and PD. For the purpose of this literature review, we chose the most prominent NMSs, namely, olfactory disorders, sleep disorders, mood disorders, psychosis, dysautonomia, and cognitive impairment. We excluded cognitive impairment and mental retardation in LSDs, as these are not symptoms in PD patients. We performed a literature search using the National Library of Medicine database (PubMed). However, it should be noted that the terminology used to describe NMSs in LSDs is often rather vague; thus, direct comparison with NMSs in PD is difficult and requires careful analysis of the described symptoms. Moreover, because LSDs are rare, large clinical studies for many of them are not available or are limited to a small number of patients. The presence of NMSs such as olfactory or autonomic dysfunction may be overlooked because they are usually not the main symptom. Thus, for LSD patients, we focus mainly, but not exclusively, on GD and GM2 gangliosidosis, as these 2 are the best studied with regard to NMSs.