SHLP2 mutation halves the odds of developing Parkinson’s
Mouse study findings may offer new insight to treat the disease
People who carry a specific mutation in the gene for a small protein called SHLP2 are about half as likely to develop Parkinson’s disease, a study from the University of Southern California (USC) has found, offering a new direction to treat the disease.
The mutation, found mainly in people of European ancestry, causes the protein to become more stable and provide increased protection against mitochondrial dysfunction — a mechanism often seen to go awry in Parkinson’s. Mitochondria are responsible for cells’ energy production.
“This study advances our understanding of why people might get Parkinson’s and how we might develop new therapies for this devastating disease,” Pinchas Cohen, MD, a professor at the USC Leonard Davis School, said in a university press release.
The study, “A naturally occurring variant of SHLP2 is a protective factor in Parkinson’s disease,” was published in the journal Molecular Psychiatry.
Mitochondria play a pivotal role in cellular energy production by transforming the energy derived from food into a usable form, which is why they often are called the cell’s powerhouses. Problems with how mitochondria work have been implicated in a range of diseases, including Parkinson’s.
Cohen, who led the study, first discovered SHLP2 in 2016 as a microprotein (small protein) made within the cell’s mitochondria. Mitochondria have their own DNA, which differs from the DNA of the nucleus, which is the cell’s control center.
“Because most research is done on well-established protein-coding genes in the nucleus, it underscores the relevance of exploring mitochondrial-derived microproteins as a new approach to the prevention and treatment of diseases of aging,” Cohen said.
Earlier work at Cohen’s lab established that SHLP2 protects against aging-related diseases and that its levels appear to increase to counteract Parkinson’s, but often fail to tag along as the disease progresses.
Researchers scanned the mitochondrial DNA of thousands of people in the U.S. who identified as white or Caucasian to look for mutations in the SHLP2-coding gene. Comparing the mitochondrial DNA in people with Parkinson’s disease and those without, they identified a mutation called m.2158 T > C that results in one amino acid (a protein building block) being replaced with a different amino acid at that position. The mutation, a variant present in 1% of Europeans, causes the protein to become more stable, helping to protect nerve cells from death.
Disease risk lowered by 50%
This variant significantly lowered the risk of Parkinson’s disease, reducing it to 50% of the average risk. The mutation was linked to higher total and low-density lipoprotein (LDL) cholesterol. (Lower total and LDL, or “bad” cholesterol, are risk factors for Parkinson’s.)
Computer modeling predicted that this variant caused a change in how SHLP2 takes on its shape. Because it becomes more stable, mutated SHLP2 was found in mitochondria at higher levels than its wild-type (normal) version.
Mitochondria rely on the activity of protein complexes to derive most of their energy. SHLP2 was found to interact with an enzyme called mitochondrial complex 1, the first player in a multi-step process to generate high-energy molecules in cells.
To understand if SHLP2 may protect against problems with the way cells get energy, the researchers used lab-grown cells with about half the levels of TFAM, a mitochondrial DNA-binding protein that also appears to be reduced in people with Parkinson’s.
Lack of TFAM caused mitochondria to become enlarged, a sign that they may be damaged. Treatment with mutated SHLP2, but not wild-type SHLP2, resulted in a significant reduction of the number of cells with enlarged mitochondria. It also protected cells from death.
Mouse model details
Researchers used a mouse model of Parkinson’s disease whereby symptoms are induced with a chemical called MPTP, which is toxic to nerve cells.
Starting five days before treatment with MPTP, mice were given injections of either mutated or wild-type SHLP2 into the belly twice daily, or left untreated. Compared with untreated mice, both versions of SHLP2 resulted in increased levels of dopamine — the chemical messenger lost during Parkinson’s progression.
However, mutated SHLP2 outperformed the wild-type protein in increasing the levels of tyrosine hydroxylase, a key enzyme in the production of dopamine. This suggests that wild-type SHLP2 “did not provide a similar degree of protection,” the researchers wrote.
“Our data highlights the biological effects of a particular gene variant and the potential molecular mechanisms by which this mutation may reduce the risk for Parkinson’s disease,” said Su-Jeong Kim, PhD, the study’s first author.
Kim, who is an adjunct research professor at the USC Leonard Davis School, added “these findings may guide the development of therapies and provide a roadmap for understanding other mutations found in mitochondrial microproteins.”