Alterations in certain types of fat in a brain area called the substantia nigra may result in elevated levels of the GPNMB protein and drive neurodegeneration in Parkinson’s disease patients, according to Harvard researchers.
The study, titled “The glycoprotein GPNMB is selectively elevated in the substantia nigra of Parkinson’s disease patients and increases after lysosomal stress,” appeared in the journal Neurobiology of Disease.
The GPNMB protein has a well-known role in driving tumor progression by suppressing immune responses. The protein is also thought to regulate inflammatory responses associated with neurodegenerative disorders, possibly exerting neuroprotective effects.
Variations in the GPNMB gene have been associated with Parkinson’s disease. Altered levels of GPNMB messenger RNA — which contains the information to generate proteins — have been described in Parkinson’s patients, specifically in the substantia nigra, a brain area which controls movement and typically shows progressive loss of dopamine-producing neurons in Parkinson’s disease.
Patients with lysosomal storage disorders (LSDs), characterized by an abnormal accumulation of toxic materials in cells — have higher than normal GPNMB protein levels, which correlates with disease severity and progression.
The link between LSDs and Parkinson’s disease has been increasingly evident, as shown by dysfunctional lysosomes during the development of the disease.
Lysosomes are cellular structures that act as the waste disposal system of the cell by digesting unwanted materials. Many genetic factors underlying familial Parkinson’s play a role in the autophagy-lysosomal cell pathway, responsible for degrading misfolded, or structurally altered, proteins within cells.
Lower activity of the lysosomal enzyme glucocerebrosidase (GCase) — implicated in Gaucher disease and responsible for breaking down a type of fat called glycosphingolipid — has been reported in the substantia nigra of patients with sporadic Parkinson’s and has been suggested to drive accumulation of the protein alpha-synuclein.
Alpha-synuclein is the main component of Lewy bodies that accumulate inside nerve cells and contribute to disease. Lysosomal dysfunction is also important in aging, which is the major risk factor for Parkinson’s disease.
To further explore the correlation between GPNMB and Parkinson’s, researchers focused on potential changes in GPNMB protein levels in the substantia nigra of post-mortem Parkinson’s patients’ brains that also exhibited age-dependent reduction in GCase activity and a corresponding elevation in glycosphingolipids.
Brains from 30 sporadic Parkinson’s patients and 25 unaffected patients were used. GPNMB protein levels were markedly higher in the substantia nigra of Parkinson’s patients, but not in other brain areas. These patients had lower GCase activity and an associated elevation of glycosphingolipids in this brain region.
Both Parkinson’s patients and healthy individuals showed a trend toward increased GPNMB levels with age. However, protein levels were not associated with age of onset, duration of disease, neuronal loss, disease severity, or extent of neurofibrillary tangles inside cells, which are all characteristic of Parkinson’s disease.
In mice that displayed alpha-synuclein buildup, no GPNMB elevations or altered GCase activity were observed. But inducing lysosomal dysfunction and the accumulation of glycosphingolipids using a GCase blocker in healthy mice led to similar changes in GPNMB brain levels as that seen in Parkinson’s patients.
These mice also showed increased protein levels in brain regions displaying activation of glia (non-neuronal cells of the nervous system) consistent with neuroinflammation.
The findings indicate that GPNMB levels do not depend on changes in alpha-synuclein, but instead relate to altered lysosomal function.
“It is plausible that changes in lipids is one driver of the pathophysiological elevations of GPNMB observed in the [substantia nigra] of [Parkinson’s] patient brains,” the scientists wrote. “This is the first demonstration of region-specific elevations of GPNMB protein in Parkinson’s.”
The investigators also said the findings indicate that GPNMB as a biomarker, in concert with genetic and other risk factors, may reveal “early and late pathology relevant to Parkinson’s disease prevention and treatment.”
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