Genetic Breakthrough May Aid Parkinson's Misdiagnosis

"Yes, doctor. My dad's first fall was on his 65th birthday. He stood in the driveway and suddenly dropped backwards on his back. After he fell two more times, we came to the clinic."

The symptoms the patient's son described didn't fit the usual diagnosis of Parkinson's disease. The family noted mood changes, including outbursts of anger. When the patient tried reading, the words "jumped" at him. Instead of looking down the page with his eyes, he moved his entire head. While his hands didn't shake, he noticeably moved around more slowly.

Dad was diagnosed with Parkinson's. The doctors weren't convinced this was the right diagnosis, but it was the best they could come up with. He was given medications for Parkinson's. They treated his symptoms with physical therapy and blood thinners to prevent clots if he got injured from a fall. But his condition worsened, and he died within 10 years.

He had been misdiagnosed. He actually had progressive supranuclear palsy , a rare and aggressive neurodegenerative disease with similar symptoms to Parkinson's. The late Rev. Jesse Jackson , who died on Feb. 17, 2026, at age 84, had a similar experience of misdiagnosis .

About 6 to 10 in 100,000 people are affected by progressive supranuclear palsy, totaling around 30,000 patients in the United States. But because this disease is often misdiagnosed, the real numbers are likely higher. It shares similar symptoms with Parkinson's, making it very challenging to distinguish between the two. In fact, PSP is also called atypical parkinsonism. Moreover, the brain cells of people with PSP share similar pathological signs with 20 other neurodegenerative disorders .

There are no biological tests to screen for progressive supranuclear palsy and no therapies specifically for this disease. Patients like Jackson are stuck with treatments that don't improve their quality of life. In our recently published research , my neuroscience lab identified a potential biomarker that could help change how doctors approach this disease.

Genetics of progressive supranuclear palsy

Rare genetic changes can increase someone's risk of developing progressive supranuclear palsy.

For example, researchers found that a single mutation on the gene coding for the stress sensor protein PERK increases a person's risk of developing the disease. PERK helps relieve stress from a part of the cell that acts as a warehouse for newly made proteins. When the cell becomes stressed, PERK dials down the production of new proteins and gives this warehouse time to recover.

Many labs worked to find why this single change in DNA could unleash a devastating life sentence. My team and I had previously found that alterations in a key protein involved in neurodegenerative diseases, tau, can activate PERK , which further weaponizes abnormal tau against cells.

After identifying three other PERK mutations , the field focused on targeting PERK as a way to treat the disease. However, results were conflicting : Both increasing and decreasing PERK activity improved cell survival and brain function in animal and cell models.

Then researchers made a crucial discovery: Unlike properly functioning PERK, the mutant form of this protein could not eliminate tau clumps in the brain. This meant that the brain normally has a way to get rid of toxic tau, but this mechanism was compromised in people who have the mutation.

Treatment strategies that could change the activity of PERK, even in sick patients, could provide a way to fight this disease.

How PERK connects to PSP

My team and I wanted to understand how PERK promotes the abnormal accumulations of tau protein that causes progressive supranuclear palsy.

First, we genetically engineered cells to express normal or mutant PERK. As expected, while both forms of PERK carried out nearly identical functions, mutant PERK did not sufficiently clear out tau. Our next step was to identify which proteins PERK actually affected.

We hypothesized that both versions of PERK reduced the production of different proteins. To test this, we tagged cells with an antibiotic that attaches to newly made proteins .

Surprisingly, only four proteins differed between normal and mutant PERK cells, suggesting we'd found a potential key to understand how progressive supranuclear palsy develops and how it kills brain cells.

One of the proteins we identified, DLX1, was previously associated with the disease. After confirming that DLX1 is enriched in the brains of people with PSP, we tested how changing DLX1 levels would affect fruit flies engineered to produce high levels of tau in their brains.

We found that reducing DLX1 levels in the flies minimized the damage tau causes on cells. These findings strongly imply that DLX1 plays a role in the development of progressive supranuclear palsy.

Future of PSP treatment

Effectively treating diseases requires identifying how they damage cells at the molecular level. Early diagnosis is especially critical to opening an effective therapeutic window before irreversible damage occurs.

Our study offers the first evidence linking key proteins involved in the development of progressive supranuclear palsy, which has major implications for how it's treated and diagnosed. For example, screening for higher DLX1 levels in the brain or blood could confirm a diagnosis of the disease. Also, developing drugs that reduce DLX1 could potentially reduce symptoms in patients.

Importantly, our team identified three other proteins we are currently testing to see whether they can also offer improved diagnostic and therapeutic value. Combination therapies that target these proteins could potentially help improve patients' lives.

As researchers work toward more accurate diagnoses and treatment, patients can have more hope to alleviate the devastating consequences of progressive supranuclear palsy.

Jose Abisambra receives funding from the National Institutes of Health. Prior research funding for his work originated from the Department of Defense, the Alzheimer's Association, the Rotary Club, and the CurePSP foundation. He is a consultant for CurieBio and co-editor-in-chief of the scientific journal Brain Research.