Development of an α-synuclein knockdown peptide and evaluation of its efficacy in Parkinson’s disease models

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Parkinson’s disease (Parkinson’s disease) is a major neurodegenerative disorder. It currently lacks a clinically relevant treatment that can directly target the disease-causing processes. Current clinical approaches, like deep brain stimulation and pharmacological treatments with levodopa and dopamine agonists, only relieve symptoms. The efficacy of these treatments is largely limited by their undesirable complications and side effects. enter image description here Source: By Ajpolino via Wikipedia

Since α-synuclein is overexpressed under certain pathological conditions of PD and these upregulated proteins can interfere with many physiological processes, such as ER-to-Golgi transport, synaptic transmission, and mitochondria function and morphology, robustly knocking down the overexpressed α-synucleinmay have better neuroprotective efficacy in restoring normal cellular functions in the Parkinson’s disease brain than simply inhibiting the formation of toxic α-synuclein oligomers.

Knockdown of α-synuclein using genetic manipulations, such as antisense oligonucleotide and small interfering RNA (siRNA), has shown protection of dopaminergic neurons in various models of Parkinson’s disease.

The clinical translation of these manipulations into an efficient Parkinson’s disease therapy has however costly and uncomfortable, as it is mainly accomplished by an invasive injection or viral infection. These technologies may not be clinically practical for therapeutic use in human patients.

Here the scientists report the development of a short, BBB and plasma membrane-permeant synthetic peptide that can rapidly reduce endogenous α-synuclein via proteasomal degradation.

Using both in vitro and in vivo models of Parkinson’s disease, the scientists provide proof-of-principle evidence for using this small α-synuclein knockdown peptide as a potential Parkinson’s disease therapy.

The authors first demonstrated that the Tat-βsyn-degron peptide can specifically reduce the level of α-synuclein both in vitro and in vivo. The authors then showed that the peptide-induced α-synuclein knockdown is associated with protection of dopaminergic neurons against toxin-induced damage in a culture model of Parkinson’s disease.

Most importantly, the scientists were able to demonstrate the therapeutic potential of systemic application of the Tat-βsyn-degron peptide as an effective Parkinson’s disease treatment in two well-characterized animal models of Parkinson’s disease.

Their α-synuclein knockdown peptide (Tat-βsyn-degron) is innovative as the peptide directly targets one of the disease-causing processes, and can be expected to stop or slow down the progression of the disease.

In addition, the peptide-mediated knockdown has a clear temporal advantage over antisense or siRNA-mediated knockdown. α-synuclein is a very stable protein with a long half-life while by hijacking the endogenous proteasomal degradation system in the cell, the Tat-βsyn-degron peptide produced a rapid and robust degradation of α-synuclein protein within a few hours.

It is also interesting to note that α-synuclein is also expressed in tissues outside the central nervous system and the scientists found that a single intraperitoneal injection of the Tat-βsyn-degron peptide similarly reduced the α-synuclein expression in the kidney and the spleen of wild-type C57BL/6 mice .

A recent success in a phase 3 clinical trial has already demonstrated that a Tat-fused short peptide is not only safe, but therapeutically effective in protecting neurons against ischemic damage in humans. The authors hope this α-synuclein knockdown peptide may also have the potential to be quickly translated into the clinic as an effective disease-modifying treatment that directly targets the disease-causing process of Parkinson’s disease.

Due to the versatility of their peptide-mediated protein knockdown method, the scientists can theoretically target disease-causing cellular proteins by simply changing the protein-binding sequence of the targeting peptide. Since many human diseases, including some of the age-related neurodegenerative diseases such as ALS, Alzheimer’s disease and Huntington’s disease, are pathologically caused by gain of function of a protein due to its mutations and/or increased expression levels, the proposed study can be expected to spur the development of new therapeutics for human diseases beyond Parkinson’s disease.

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