Student ID: 829886
5. Discuss the association between glucocerebrosidase deficiency and Parkinson`s disease.
Parkinson’s disease is the second most prevalent neurological disease, behind Alzheimer’s. It
remains unclear as to the cause of the disease. Due to the obvious motor function and neurological
symptoms, it can be diagnosed in the early stages however, the treatments available currently only
allow the patient to make their symptoms more manageable, they do not slow or stop the
progression of the disease.
Parkinson’s disease is a heterogenous degenerative neurological disease that affects the deep areas
of the brain such as the basal ganglia and the substantia nigra, usually familial but it has been
hypothesised that sporadic Parkinson’s disease could be induced by environmental factors.
Neuropathologically Parkinson’s disease is characterised by filamentous inclusions in the form of
Lewy bodies, abnormal deposits of α-synuclein form the Lewy bodies (Goedert, M., 2001).
Glucocerebrosidase (GCase) is a lysosomal glycoside hydrolase that cleaves the β-glucosidic bond of
glucocerebroside (GlcCer) to glucose and ceramide, this reaction takes place in the lysosome. When
GCase is impaired GlcCer cannot be broken down, this causes an accumulation of
glucosylsphingosine which can be transported from the lysosome to the cytoplasm in which
sphingosine, sphinosine-1-phosphate as well as glucosphingosine will increase in concentration.
GlcCer will also accumulate in the cytoplasm once the concentration within the lysosome reaches
capacity. Homozygous mutations of the glucocerebrosidase gene (GBA1) has been linked to
Gaucher’s disease, a lysosomal storage disorder. When GCase is impaired a build up of GlcCer can
occur. In most cells the remaining GCase activity can degrade cellular GlcCer however, in cells such
as tissue macrophages found in the spleen, liver and bone marrow the levels of cellular GlcCer may
exceed GCase activity. Tissue macrophages remove unnecessary white blood cells (WBC) and red
blood cells (RBC) which are naturally abundant in GlcCer. Gaucher cells are defined as macrophages
with exceedingly high levels of GlcCer, caused by the accumulation from WBC/RBC and the
decreased ability of GCase.
Schapira, A. (2015) discusses how a 20-fold increase was seen in the risk for Parkinson’s disease with
homozygous or heterozygous mutations to the GBA gene. N370S and L444P are the most common
point mutations seen in Gaucher’s disease and Parkinson’s disease patients.
The neurotoxicity that occurs in Parkinson’s disease patients has been suggested to be linked to the
accumulation of glucosphingosine however no accumulation has been shown in Parkinson disease
patients’ brains. It has been observed that while GCase activity is degreased there is an increase in α-
synuclein protein. Murphy, K.E (2014) investigated the possible correlation between decreased
GCase and α-synuclein in sporadic Parkinson’s disease. Using stepwise multiple regression analysis
Murphy and team were able to determine that in the early stages of the disease the amount of
increase in α-synuclein corresponded to the reduction in lysosomal GCase activity. They also
concluded that this was only seen in selectively areas of the brain. However, in regions in which
increased α-synuclein was seen, no significant reduction in GBA1 messenger RNA was observed.
Murphy and colleagues also investigated whether changes were seen between early and late stages
of Parkinson’s disease. They concluded that even though GCase activity is decreased in early stages,
with no detectable involvement of GBA1 mRNA, sphingosine or enzyme activity, there was no
obvious changes in the late stage, GCase and GlcCer was detected to be reduced further in late
stages with no involvement of other biochemical markers.
Another theory behind the association of α-synuclein and GCase is that α-synuclein exhibits an
inhibitory effect on GCase. Mazzulli et al, (2011) discussed how a positive feedback loop mechanism
5. Discuss the association between glucocerebrosidase deficiency and Parkinson`s disease.
Parkinson’s disease is the second most prevalent neurological disease, behind Alzheimer’s. It
remains unclear as to the cause of the disease. Due to the obvious motor function and neurological
symptoms, it can be diagnosed in the early stages however, the treatments available currently only
allow the patient to make their symptoms more manageable, they do not slow or stop the
progression of the disease.
Parkinson’s disease is a heterogenous degenerative neurological disease that affects the deep areas
of the brain such as the basal ganglia and the substantia nigra, usually familial but it has been
hypothesised that sporadic Parkinson’s disease could be induced by environmental factors.
Neuropathologically Parkinson’s disease is characterised by filamentous inclusions in the form of
Lewy bodies, abnormal deposits of α-synuclein form the Lewy bodies (Goedert, M., 2001).
Glucocerebrosidase (GCase) is a lysosomal glycoside hydrolase that cleaves the β-glucosidic bond of
glucocerebroside (GlcCer) to glucose and ceramide, this reaction takes place in the lysosome. When
GCase is impaired GlcCer cannot be broken down, this causes an accumulation of
glucosylsphingosine which can be transported from the lysosome to the cytoplasm in which
sphingosine, sphinosine-1-phosphate as well as glucosphingosine will increase in concentration.
GlcCer will also accumulate in the cytoplasm once the concentration within the lysosome reaches
capacity. Homozygous mutations of the glucocerebrosidase gene (GBA1) has been linked to
Gaucher’s disease, a lysosomal storage disorder. When GCase is impaired a build up of GlcCer can
occur. In most cells the remaining GCase activity can degrade cellular GlcCer however, in cells such
as tissue macrophages found in the spleen, liver and bone marrow the levels of cellular GlcCer may
exceed GCase activity. Tissue macrophages remove unnecessary white blood cells (WBC) and red
blood cells (RBC) which are naturally abundant in GlcCer. Gaucher cells are defined as macrophages
with exceedingly high levels of GlcCer, caused by the accumulation from WBC/RBC and the
decreased ability of GCase.
Schapira, A. (2015) discusses how a 20-fold increase was seen in the risk for Parkinson’s disease with
homozygous or heterozygous mutations to the GBA gene. N370S and L444P are the most common
point mutations seen in Gaucher’s disease and Parkinson’s disease patients.
The neurotoxicity that occurs in Parkinson’s disease patients has been suggested to be linked to the
accumulation of glucosphingosine however no accumulation has been shown in Parkinson disease
patients’ brains. It has been observed that while GCase activity is degreased there is an increase in α-
synuclein protein. Murphy, K.E (2014) investigated the possible correlation between decreased
GCase and α-synuclein in sporadic Parkinson’s disease. Using stepwise multiple regression analysis
Murphy and team were able to determine that in the early stages of the disease the amount of
increase in α-synuclein corresponded to the reduction in lysosomal GCase activity. They also
concluded that this was only seen in selectively areas of the brain. However, in regions in which
increased α-synuclein was seen, no significant reduction in GBA1 messenger RNA was observed.
Murphy and colleagues also investigated whether changes were seen between early and late stages
of Parkinson’s disease. They concluded that even though GCase activity is decreased in early stages,
with no detectable involvement of GBA1 mRNA, sphingosine or enzyme activity, there was no
obvious changes in the late stage, GCase and GlcCer was detected to be reduced further in late
stages with no involvement of other biochemical markers.
Another theory behind the association of α-synuclein and GCase is that α-synuclein exhibits an
inhibitory effect on GCase. Mazzulli et al, (2011) discussed how a positive feedback loop mechanism
