Cationic Carbosilane Dendrimers Prevent Abnormal α-Synuclein Accumulation in Parkinson's Disease Patient-Specific Dopamine Neurons.

Abstract

Accumulation of misfolded α-synuclein (α-syn) is a hallmark of Parkinson's disease (PD) thought to play important roles in the pathophysiology of the disease. Dendritic systems, able to modulate the folding of proteins, have emerged as promising new therapeutic strategies for PD treatment. Dendrimers have been shown to be effective at inhibiting α-syn aggregation in cell-free systems and in cell lines. Here, we set out to investigate the effects of dendrimers on endogenous α-syn accumulation in disease-relevant cell types from PD patients. For this purpose, we chose cationic carbosilane dendrimers of bow-tie topology based on their performance at inhibiting α-syn aggregation in vitro. Dopamine neurons were differentiated from induced pluripotent stem cell (iPSC) lines generated from PD patients carrying the LRRK2G2019S mutation, which reportedly display abnormal accumulation of α-syn, and from healthy individuals as controls. Treatment of PD dopamine neurons with non-cytotoxic concentrations of dendrimers was effective at preventing abnormal accumulation and aggregation of α-syn. Our results in a genuinely human experimental model of PD highlight the therapeutic potential of dendritic systems and open the way to developing safe and efficient therapies for delaying or even halting PD progression.

• Authors: Raquel Ferrer-Lorente, Tania Lozano-Cruz, Irene Fernández-Carasa, Katarzyna Miłowska, Francisco Javier de la Mata, Maria Bryszewska, Antonella Consiglio, Paula Ortega, Rafael Gómez, Angel Raya
• Journal: Biomacromolecules (Biomacromolecules) Vol. 22 Issue 11 Pg. 4582-4591 (11 08 2021) ISSN: 1526-4602 [Electronic] United States
• PMID: 34613701 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)

Chemical References

• Dendrimers
• SNCA protein, human
• Silanes
• alpha-Synuclein
• carbosilane
• LRRK2 protein, human
• Leucine-Rich Repeat Serine-Threonine Protein Kinase-2

Topics

• Dendrimers (pharmacology)
• Dopaminergic Neurons
• Humans
• Leucine-Rich Repeat Serine-Threonine Protein Kinase-2
• Parkinson Disease (drug therapy, genetics)
• Silanes
• alpha-Synuclein (genetics)