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Science vs. neuro-degeneration


Date: April 30, 2020
Weizmann Magazine Vol. 17

Two Weizmann Institute labs have taken the lead in the battle against neurodegeneration, with discoveries that may eventually contribute to treatments—or even cures—for two separate conditions: Huntington’s disease (HD) and Amyotrophic lateral sclerosis (ALS), also known as Lou Gehrig’s disease.

Huntington’s disease is a fatal genetic disorder caused by mutations in the huntingtin gene, leading to the progressive breakdown of nerve cells in the brain. Often striking in the prime of life and causing deterioration of both physical and cognitive abilities, HD currently has no cure.

Now, Prof. Rivka Dikstein of the Department of Biomolecular Sciences has identified two molecules that can block the activity of Spt5, a gene involved in HD onset.  A regulator of gene transcription—an early stage in the process that leads to protein production—Spt5 is specifically required for transcribing the mutant huntingtin gene associated with HD progression.

A team led by Dr. Anat Bahat, a staff scientist in the Dikstein lab, screened a library of about 100,000 small molecules, and discovered two molecules that bind to Spt5 and block the expression of the mutated protein. However, in cases where the huntingtin gene appears in its normal, non-mutated form, these molecules allow protein expression to occur. These findings represent an important step forward in the eventual development of a drug capable of “short circuiting” a molecular dynamic that drives Huntington’s disease.

In a separate advance, Prof. Eran Hornstein of the Department of Molecular Genetics recently discovered a molecule involved in the onset of ALS. Prof. Hornstein and his colleagues led a large international collaboration that identified a microRNA gene that plays a crucial role in motor neurons. This microRNA gene is expressed at lower levels in ALS patients as compared to healthy individuals—something that makes it a powerful biomarker for early ALS diagnosis. The team also identified rare mutations in the gene that codes for this ALS-associated microRNA.

Prof. Hornstein’s research could lead the way toward new strategies in which the microRNA he and his colleagues discovered would be used to mediate ALS symptoms, thereby transforming ALS from a death sentence into a chronic, manageable illness.