In late-stage Parkinson’s disease, the drug levodopa becomes less effective in treating symptoms because of the inexorable loss of dopamine-releasing neurons. But a new preclinical study shows a gene therapy targeting the small brain region where these neurons reside, the substantia nigra, substantially boosts the benefits of levodopa.
The gene therapy restored the ability of neurons in the substantia nigra to convert levodopa to dopamine. In essence, this allowed levodopa to recreate the environment found in the healthy brain and eliminated the aberrant brain activity responsible for difficulty in moving.
In the same study, scientists also provide an explanation for why dopamine-releasing neurons are lost in the disease. Using advanced genetic tools, the authors show that damage to the powerplants inside dopamine-releasing neurons (mitochondria) is sufficient to trigger a sequence of events that faithfully recapitulates what happens to brain circuits in Parkinson’s disease.
The findings in mice published in Nature, may help identify humans in the earliest stages of Parkinson’s disease, develop therapies to slow disease progression and treat late-stage disease.
The key new findings:
Damage to the power plants in dopamine-releasing neurons is enough to cause Parkinson’s disease. When these power plants (mitochondria) begin to shut down, the ability of neurons to do their jobs in the brain is compromised. Without a sufficient source of energy, neurons eventually wither and die. This finding opens a new path to develop therapies to protect the function of mitochondria.
Contrary to the past 30 years of thinking, the emergence of the motor symptoms of Parkinson’s disease requires the loss of dopamine release in a small region of the brain called the substantia nigra. This discovery also opens the door to new therapies for late-stage Parkinson’s disease patients.
Scientists demonstrated that a gene therapy targeting the substantia nigra effectively boosts the symptomatic benefit of levodopa.
“The development of effective therapies to slow or stop Parkinson’s disease progression requires scientists know what causes it,” said the lead study author. “This is the first time there has been definitive evidence that injury to mitochondria in dopamine-releasing neurons is enough to cause a human-like parkinsonism in a mouse.
“Whether mitochondrial damage was a cause or consequence of the disease has long been debated. Now that this issue is resolved, we can focus our attention on developing therapies to preserve their function and slow the loss of these neurons.”
In addition to providing a clear target for disease-modifying therapies, the study provides a model of Parkinson’s disease before clinical symptoms appear. The slow, progressive loss of dopamine-releasing neurons in the model allowed researchers to see what may be happening in the brain well before movement becomes difficult.
“This new ‘human-like’ model may help us develop tests that would identify people who are on their way to being diagnosed with Parkinson’s disease in five or 10 years,” the lead said. “Doing so would allow us to get them started early on therapies that could alter disease progression.”
https://www.nature.com/articles/s41586-021-04059-0
Disruption of mitochondrial complex I induces progressive parkinsonism
- 1,262 views
- Added
Edited
Latest News
Protein found in brain link…
By newseditor
Posted 09 Dec
Calcium acts as missing lin…
By newseditor
Posted 09 Dec
How repeated traumatic brai…
By newseditor
Posted 08 Dec
Metformin rescues neuronal…
By newseditor
Posted 08 Dec
Variants in the genome inte…
By newseditor
Posted 08 Dec
Other Top Stories
How secondary structure RNA elements control the cleavage activity…
Read more
Transcription factors regulate distinct segments of the distal neph…
Read more
Single-molecule FRET illuminate mechanisms of GPCR activation
Read more
How hormones define brain sex differences
Read more
CDC7-independent G1/S transition revealed by targeted protein degra…
Read more
Protocols
Brain-wide circuit-specific…
By newseditor
Posted 05 Dec
Cheap, cost-effective, and…
By newseditor
Posted 03 Dec
Temporally multiplexed imag…
By newseditor
Posted 02 Dec
Efficient elimination of ME…
By newseditor
Posted 01 Dec
Personalized drug screening…
By newseditor
Posted 30 Nov
Publications
Extracellular calcium funct…
By newseditor
Posted 09 Dec
TAF15 amyloid filaments in…
By newseditor
Posted 09 Dec
Metformin rescues migratory…
By newseditor
Posted 08 Dec
Oral magnesium prevents ace…
By newseditor
Posted 08 Dec
GDF15 is a major determinan…
By newseditor
Posted 08 Dec
Presentations
Hydrogels in Drug Delivery
By newseditor
Posted 12 Apr
Lipids
By newseditor
Posted 31 Dec
Cell biology of carbohydrat…
By newseditor
Posted 29 Nov
RNA interference (RNAi)
By newseditor
Posted 23 Oct
RNA structure and functions
By newseditor
Posted 19 Oct
Posters
A chemical biology/modular…
By newseditor
Posted 22 Aug
Single-molecule covalent ma…
By newseditor
Posted 04 Jul
ASCO-2020-HEALTH SERVICES R…
By newseditor
Posted 23 Mar
ASCO-2020-HEAD AND NECK CANCER
By newseditor
Posted 23 Mar
ASCO-2020-GENITOURINARY CAN…
By newseditor
Posted 23 Mar