Impaired activity of the enzyme glucocerebrosidase (GCase), which is responsible for breaking down and recycling cell waste, boosts neurodegeneration and accumulation of alpha-synuclein in Parkinson’s, according to a new mouse study.
The research, “Development and biochemical characterization of a mouse model of Parkinson’s disease bearing defective glucocerebrosidase activity,” was published in the journal Neurobiology of Disease.
Mutations in both copies (homozygous) of the GBA1 gene are responsible for the development of Gaucher disease, a disorder characterized by impaired activity of GCase — an enzyme responsible for the breakdown of a lipid, called glucosylceramide, inside cells.
If occurring in only one gene copy (heterozygous), mutations in GBA1 do not cause Gaucher, but are considered the most relevant risk factor for Parkinson’s after reaching advanced age. Nearly 10 percent of patients with sporadic Parkinson’s disease have heterozygous GBA1 mutations, showing more severe cognitive decline and a slightly younger age of onset compared to those without such mutations.
A link between the hallmark Parkinson’s protein alpha-synuclein and GCase has been suggested by the observation of a mutant form of this enzyme in Lewy bodies (protein clumps mainly formed by aggregates of alpha-synuclein). Also, prior studies have shown that inhibiting GCase activity boosts alpha-synuclein accumulation and activation of cells called microglia, a sign of neuroinflammation seen in patients with Parkinson’s disease.
Researchers at the IRCCS Mondino Foundation, in Italy, aimed to better understand the association between GCase deficiency and Parkinson’s. Specifically, they explored whether a partial defect in GCase comparable to that caused by heterozygous mutations in GBA1 (with approximately 50 percent of residual GCase activity) may increase the effects of MPTP, a widely used neurotoxin to cause Parkinson’s in animal models.
The team developed a model with partial deficiency of GCase activity caused by chronic (28 days) administration of low doses of CBE — a GCase inhibitor — in mice injected with MPTP for five days.
They then determined brain GCase activity, degeneration of dopamine-producing neurons in the nigrostriatal pathway, alpha-synuclein levels, and neuroinflammation. Of note, progressive degeneration of the brain’s nigrostriatal pathway — one of the four major dopamine pathways in the brain, involved in production of movement — is a characteristic event in Parkinson’s.
The results showed that a CBE dose of 50 mg/kg of body weight caused GCase activity reduction in the cerebral cortex similar to that seen in Parkinson’s patients with heterozygous GCase mutations.
The team then found that, although not statistically significant, pre-treatment with this CBE dose boosted MPTP-induced neurodegeneration in the striatum. This was assessed by the amount and signal of tyrosine hydroxylase — the enzyme that mediates the production of the dopamine precursor L-DOPA — as well as by the number of neurons containing this enzyme.
“Our results confirm the concept that GCase dysfunction renders nigrostriatal neurons more susceptible to neurodegeneration,” researchers wrote.
Also, using both CBE and MPTP was able to cause a significant increase in the number of dopamine-producing neurons expressing alpha-synuclein in the substantia nigra, leading to the initiation of the process of alpha-synuclein primary aggregation. Of note, the substantia nigra is a brain region that contains dopaminegic neurons, which are lost as a consequence of Parkinson’s disease.
In turn, microglia was markedly activated by either CBE or MPTP within the substantia nigra. Co-administration of these two compounds did not promote further activation, which the investigators attributed to all microglia cells already being activated by each compound separately.
“Overall, we believe this model may be used as an additional tool to study the biochemical processes underlying pathophysiology [changes of normal physiological functions associated with disease] characterizing [Parkinson’s] in the presence of GCase defects,” researchers wrote.