# Peptidomimetics Activating the Proteasome: A New Perspective for Parkinson’s Treatment

## TL;DR

This paper introduces peptidomimetics that activate the proteasome, potentially offering a new treatment for Parkinson's by reducing harmful protein aggregates.

## Contribution

The study presents novel peptidomimetics that effectively stimulate proteasome activity and reduce disease-related protein aggregates.

## Key findings

- Peptidomimetics effectively stimulate proteasome activity in biochemical and cell culture assays.
- They reduce phosphorylated α-synuclein aggregates in hippocampal neurons without cytotoxicity.
- Compounds are stable in human plasma and can penetrate cell membranes.

## Abstract

The development of
age-related neurodegenerative diseases is associated
with the accumulation of damaged and misfolded proteins. Such proteins
are eliminated from cells by proteolytic systems, mainly by 20S proteasomes,
whose activity declines with age. Its stimulation has been recognized
as a promising approach to delay the onset or ameliorate the symptoms
of neurodegenerative disorders. Here we present peptidomimetics that
are very effective in stimulating the proteasome in biochemical assays
and in cell culture. They are stable in human plasma and capable of
penetrating the cell membranes. The activators demonstrated the ability
to enhance h20S degradation of α-synuclein and tau, whose aggregates
are involved in the development of Parkinson’s and Alzheimer’s
diseases, respectively. The peptidomimetics did not show cytotoxicity
to HEK293T and primary hippocampal cells. Additionally, these compounds
were highly effective in reducing the amount of phosphorylated α-synuclein
aggregates in hippocampal neurons in a mouse embryonic cell model.