- A class of drugs that treats other cancers found
beneficial for the treatment of Amyotrophic Lateral Sclerosis (ALS) and Frontotemporal degeneration (FTD)
- These cancer drugs inhibit
poly (ADP-ribose) polymerase and prevent toxic accumulations of proteins in the
cytoplasm of the neurons
inhibitors could be optimized as valuable cancer therapeutic for brain diseases
in the future
A class of drugs used to treat cancer has been recently found to be
beneficial in treating and preventing brain disorders, particularly Lou
Gehrig's disease or amyotrophic lateral
, and some forms of frontotemporal degeneration
to research conducted in the School of Arts and Sciences and the Perelman
School of Medicine at the University of Pennsylvania.
‘A drug in development as cancer therapeutic could be potentially used to prevent the formation of harmful TDP-43 clumps in cells, according to new research.’
The class of drugs are
inhibitors of the enzyme, poly ADP ribose polymerase (PARP)
, and are hence known as PARP inhibitors
. They halt the misplacement of specific proteins
called TDP-43 that affect nerve cells.
The study is published in the journal, Molecular Cell
Background on the
connection between TDP-43, stress granules, ALS and FTD
- TDP-43 proteins are DNA-binding proteins that
usually reside in the nucleus of the cell. It is the primary pathological
protein in both ALS and FTD.
- There is evidence that ALS and FTD are closely
related conditions with overlapping clinical, genetic and
neuropathological features. ALS involves degeneration of motor neurons,
and FTD involves degeneration of cortical neurons.
- When TDP-43 mistakenly goes outside the nucleus
into the cytoplasm, it forms clumps in the brain cells or cytoplasmic
aggregates, in the regions of the central nervous system that are affected
in ALS and FTD.
- When TDP-43 binds to another molecule, poly (ADP-ribose) or PAR, it
accumulates inside several cellular structures called stress granules
(SGs). SGs are cytoplasmic RNA granules that are formed in response to various external stimuli and are essential
to cell survival following stress. SGs have been studied in ALS and FTD.
- The initial accumulation does not cause imminent
harm to a cell, but after a prolonged period, TDP-43 changes into
structures that are observed in brain diseases.
Study - To understand the
effect of PARP inhibitors on TDP-43 proteins
- The team found that TDP-43 can change from a
soluble form to a concentrated liquid form by interacting with other
TDP-43 molecules and binding non-covalently with macromolecules like PAR.
- Binding of TDP-43 with PAR promotes liquid-liquid
phase separation of TDP-43 which is required for its accumulation inside
stress granules present in mammalian cells and neurons.
- Initially, being inside the stress granules
protects TDP-43 from disease-associated phosphorylation.
- However, when there is long-term stress, the
stress granules resolve and leave behind the aggregates of phosphorylated
- The soluble or the liquid form of TDP-43 is
characteristic of a stress granule and hence likely beneficial. However,
when the TDP-43 molecules become solidified with time, they can be
difficult to remove.
inhibitors are used, there is a reduction in the levels of PARP that in turn
reduces TDP-43 accumulation in the cytoplasm and potently reduces
The small inhibitor molecules inhibit the formation of cytoplasmic
TDP-43 aggregates without affecting stress granule assembly. In this process,
they stop TDP-43-associated pathology and neurodegeneration and could have
therapeutic utility for ALS and FTD.
ALS and FTD-TDP-43 can be devastating for the patient and family, and
there are limited treatment options. "What excited me about pursuing this
pathway was the promise of small molecules that attack the disease process of
TDP-43," said lead author Leeanne McGurk, PhD, a research associate in
Bonini's lab. "When I tested them on cultured cells, I found they could
alleviate the build-up of TDP-43 that mirrors the abnormal protein
we see in disease."
team's findings could provide the next step for neurologists to look for
new ways to fight neurodegenerative disorders like ALS.
- Leeanne McGurk, Edward Gomes, Lin Guo, Jelena Mojsilovic-Petrovic, Van Tran, Robert G. Kalb, James Shorter, Nancy M. Bonini. "Poly (ADP-Ribose) Prevents Pathological Phase Separation of TDP-43 by Promoting Liquid Demixing and Stress Granule Localization". Molecular Cell, (2018); DOI: 10.1016/j.molcel.2018.07.002