A new compound called CLR01, which works like a “molecular tweezer” to clear toxic protein clumps that accumulate in brain cells, could become a promising therapy to slow Parkinson’s disease progression, a study suggests.
The study, “CLR01 protects dopaminergic neurons in vitro and in mouse models of Parkinson’s disease,” was published in the journal Nature Communications.
Parkinson’s is characterized by motor and non-motor symptoms caused by the death of midbrain dopamine-producing neurons. These nerve cells are thought to die as a consequence of the toxic aggregation, or clumping together, of a protein called alpha-synuclein in small fiber-like (insoluble fibril) structures known as Lewy bodies.
CLR01 works as a sort of molecular tweezer: its “C” shape allows it to wrap around chains of lysine — an amino acid that is present in nearly all proteins — and disrupt the formation of protein clumps that affect the normal functioning of nerve cells, or neurons.
A recent collaborative study, led by University of Oxford researchers, investigated CLR01’s ability to reduce the formation of protein clumps in cell and mouse models of Parkinson’s.
“Our work is focused on developing new approaches to saving neurons when they start to lose function early on, but before they die later on in the condition,” Richard Wade-Martins, PhD, head of the Oxford Parkinson’s Disease Centre and lead author of the study, said in a press release.
The researchers began by analyzing CLR01’s effect on the aggregation of alpha-synuclein in the lab (in vitro), using electron microscopy.
The compound was able to block such clumping and also separate small alpha-synuclein aggregates, such as oligomers and fibrils, which are known to contribute to disease progression. Moreover, in protein brain extracts from Parkinson’s patients, CLR01 also was able to reduce alpha-synuclein clumps.
To further explore the therapeutic potential of CLR01, the researchers then tested its ability to reduce alpha-synuclein clumping and toxicity in dopaminergic neurons derived from induced pluripotent stem cells (iPSCs): skin or blood cells that have been reprogrammed back into a stem cell-like state.
When cultured in the presence of Lewy body extracts, these cells showed features of axonal degeneration, or the impairment of brain pathways known as axons. This toxicity, however, was rescued upon CLR01 treatment.
CLR01 also was able to efficiently break up oligomers and/or prevent their clumping in a dose-dependent manner. The scientists also tested a CLR01 investigatory inactive analog called CLR03, but it did not have a significant effect on alpha-synuclein aggregation.
To test whether CLR01 could reduce alpha-synuclein clumping and toxicity in other neural populations, the researchers treated primary rat neuronal and astrocytic (another type of nerve cell) cultures with Lewy body extracts in the presence or absence of CLR01. Treatment with the compound was able to prevent cell death induced by the presence of Lewy body extracts in the neuronal cultures, but not in those of astrocytes.
Altogether, these data suggest that CLR01 is able to reduce alpha-synuclein clumping and toxicity in both human and rat cell cultures.
Alpha-synuclein was found to be actively transported along axons — the long arms that project from neurons’ bodies and allow them to transport molecules between nerve cells. CLR01 was able to protect neurons from alpha-synuclein clumping by reducing its interactions with specific proteins that are responsible for transporting molecules across axons.
The researchers then performed studies in live animals (in vivo), using a mouse model of early stage Parkinson’s that stimulates the formation of protein clumps and mimics motor symptoms.
Year-old mice were treated for two months with CLR01, injected under the skin. Meanwhile, older animals (18 months old) were implanted with a mini-pump under their skin that released CLR01. This was done to minimize manipulation and stress among the aged animals.
The results showed that treatment with CLR01 was able to rescue motor behavior defects, and reduce alpha-synuclein aggregates and oligomeric accumulation in 1-year-old animals, but only partially in older animals. This showed that CLR01’s effects are age-dependent and that the timing of treatment is critical when considering a possible CLR01 use in the clinic.
Finally, the researchers tested two different alpha-synuclein intracranial injection models representing more late-stage disease. In both models, CLR01 reduced alpha-synuclein aggregation, demonstrating its broad therapeutic potential.
The team believes that molecular tweezers such as CLR01 are highly promising candidates for the treatment of Parkinson’s.
“These findings show that this innovative ‘molecular tweezer’ approach has exciting potential in the lab,” said Beckie Port, research manager at Parkinson’s UK.
“‘We desperately need treatments that protect brain cells in Parkinson’s,” Port said. “We now need to take this therapy forward to test in clinical trials — only then will we know whether it can do the same in people with Parkinson’s.”
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