We use cookies to understand how you use our site and to improve your experience. This includes personalizing content and advertising. To learn more, click here. By continuing to use our site, you accept our use of cookies. Cookie Policy.

Features Partner Sites Information LinkXpress
Sign In
Advertise with Us
LGC Clinical Diagnostics

Download Mobile App




Nilotinib Enhances Toxic Protein Removal from Parkinson's Disease Neurons

By LabMedica International staff writers
Posted on 21 May 2013
Print article
Image: Senior author Dr. Charbel E-H Moussa (Photo courtesy of Georgetown University Medical Center).
Image: Senior author Dr. Charbel E-H Moussa (Photo courtesy of Georgetown University Medical Center).
The anticancer drug nilotinib induces clearance of the toxic protein alpha-synuclein from neurons in a mouse model of Parkinson's disease and ameliorates symptoms of the disease.

Parkinson's disease is a movement disorder characterized by death of dopaminergic substantia nigra (SN) neurons and brain accumulation of the protein alpha-synuclein.

Investigators at Georgetown University Medical Center (Washington DC, USA) worked with a mouse model of Parkinson’s disease. They reported in the May 10, 2013, online edition of the journal Human Molecular Genetics that lentiviral transfection of the gene encoding alpha-synuclein into the mouse SN lead to activation (phosphorylation) of the tyrosine kinase Abl and that lentiviral transfection of the gene encoding Abl increased alpha-synuclein levels, which exacerbated the disease. Administration of the tyrosine-kinase inhibitor nilotinib decreased Abl activity and increased autophagic clearance of alpha-synuclein into lysosomes in transgenic and lentiviral gene-transfer models.

The drug nilotinib was approved as Tasigna in the USA and the EU for drug-resistant chronic myelogenous leukemia (CML). In 2006, a Phase I clinical trial found that nilotinib had a relatively favorable safety profile and showed activity in cases of CML resistant to treatment with imatinib (Gleevec [USA]/ Glivec [Europe, Australia, and Latin America]), another tyrosine kinase inhibitor currently used as a first-line treatment. In that study, 92% of patients (already resistant or unresponsive to imatinib) achieved a normal white blood cell counts after five months of treatment.

In the current study, nilotinib, which enters the brain within [US] Food and Drug Administration approved doses, led to autophagic degradation of alpha-synuclein, protection of SN neurons and improvement of motor performance in the Parkinson's disease mice.

"No one has tried anything like this before," said senior author Dr. Charbel E-H Moussa, assistant professor of neuroscience at the Georgetown University Medical Center. "This drug, in very low doses, turns on the garbage disposal machinery inside neurons to clear toxic proteins from the cell. By clearing intracellular proteins, the drug prevents their accumulation in pathological inclusions called Lewy bodies and/or tangles, and also prevents amyloid secretion into the extracellular space between neurons, so proteins do not form toxic clumps or plaques in the brain."

"The doses used to treat CML are high enough that the drug pushes cells to chew up their own internal organelles, causing self-cannibalization and cell death," said Dr. Moussa. "We reasoned that small doses—for these mice, an equivalent to 1% of the dose used in humans—would turn on just enough autophagy in neurons that the cells would clear malfunctioning proteins, and nothing else. We successfully tested this for several diseases models that have an accumulation of intracellular protein. It gets rid of alpha-synuclein and tau in a number of movement disorders, such as Parkinson's disease as well as Lewy body dementia."

Related Links:

Georgetown University Medical Center


Platinum Member
COVID-19 Rapid Test
OSOM COVID-19 Antigen Rapid Test
HLX
Complement 3 (C3) Test
GPP-100 C3 Kit
Gold Member
Real-time PCR System
GentierX3 Series

Print article

Channels

Molecular Diagnostics

view channel
Image: A simple method can predict risk of worsening of widespread kidney disease (Photo courtesy of 123RF)

Simple Measurement Predicts Risk of Rapid Progression of Chronic Kidney Disease

Chronic kidney disease (CKD) is increasingly becoming a major health issue worldwide. For those diagnosed with CKD, the rate of disease progression can vary, with some individuals experiencing a rapid... Read more

Hematology

view channel
Image: The Gazelle Hb Variant Test (Photo courtesy of Hemex Health)

First Affordable and Rapid Test for Beta Thalassemia Demonstrates 99% Diagnostic Accuracy

Hemoglobin disorders rank as some of the most prevalent monogenic diseases globally. Among various hemoglobin disorders, beta thalassemia, a hereditary blood disorder, affects about 1.5% of the world's... Read more

Pathology

view channel
Image: The photoacoustic spectral response sensing instrument is based on low-cost laser diodes (Photo courtesy of Khan et al., doi 10.1117/1.JBO.29.1.017002)

Compact Photoacoustic Sensing Instrument Enhances Biomedical Tissue Diagnosis

The pursuit of precise and efficient diagnostic methods is a top priority in the constantly evolving field of biomedical sciences. A promising development in this area is the photoacoustic (PA) technique.... Read more

Industry

view channel
Image: The companies will develop genetic testing systems based on capillary electrophoresis sequencers (Photo courtesy of 123RF)

Sysmex and Hitachi Collaborate on Development of New Genetic Testing Systems

Sysmex Corporation (Kobe, Japan) and Hitachi High-Tech Corporation (Tokyo, Japan) have entered into a collaboration for the development of genetic testing systems using capillary electrophoresis sequencers... Read more
Copyright © 2000-2024 Globetech Media. All rights reserved.