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 LRRK2 G2019S 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.

Air Pollution, Ultrafine Particles, and Your Brain: Are Combustion Nanoparticle Emissions and Engineered Nanoparticles Causing Preventable Fatal Neurodegenerative Diseases and Common Neuropsychiatric Outcomes?

“…67,68 This information should lay a theoretical foundation for prevention of neurological fatal diseases. 68 We are deeply concerned with (i) cognitive and/or psychomotor dysfunction, common findings in children exposed to air pollution, and (ii) brain MRI showing white matter, cortical and volumetric changes, and/or lower functional integration and segregation in children's brain networks 5,69,70 that could represent neurodegenerative early changes. In 3133 preadolescents from a Rotterdam, Netherlands birth cohort, structural brain MRI images were obtained at age 9−12 years, and associations between pregnancy and childhood air pollution exposures were recorded with smaller corpus callosum, nucleus accumbens, and hippocampus, and larger amygdala and cerebellum per 1 ng/m 3 increase in pregnancy exposure to polycyclic aromatic hydrocarbons.…”

“…We need to understand air pollution components, including UFP and NP (combustion-derived, industrial, food related, and more) and underlying mechanisms of post-translational modifications of critical neural proteins. UFP and NP share specific effects upon phosphorylation, ubiquitination, and nitration, all processes altered in AD, PD, and TDP-43 pathogenesis. , This information should lay a theoretical foundation for prevention of neurological fatal diseases . We are deeply concerned with (i) cognitive and/or psychomotor dysfunction, common findings in children exposed to air pollution, and (ii) brain MRI showing white matter, cortical and volumetric changes, and/or lower functional integration and segregation in children’s brain networks ,, that could represent neurodegenerative early changes.…”

Carbosilane dendritic nanostructures, highly versatile platforms for pharmaceutical applications

“…Several studies have shown that the topology of the dendritic system is a key factor in protein interaction to avoid aggregation. For example, in Parkinson's disease, bow‐tie dendrimers (Figure S2) prevent the abnormal accumulation of α‐synuclein in dopamine neurons at noncytotoxic concentrations (Figure 2, left), while the spherical and dendritic wedge topologies (Figure S3) did not show any effect (Ferrer‐Lorente et al, 2021). However, in the prevention of β‐amyloid aggregates in pancreatic islets isolated from Tg‐hIAPP mice, the dendritic wedge was the most promising system (Figure 2, right; Lozano‐Cruz et al, 2020).…”

“…Effect of cationic CBS dendrimers on the abnormal accumulation of α‐synuclein in dopamine neurons from Parkinson's disease patients (left, Copyright ACS 2021; Ferrer‐Lorente et al, 2021) and on the amyloid severity on type‐2 diabetes (right, Copyright Wiley 2020; Lozano‐Cruz et al, 2020). …”

A Dual Synergetic Nanoreactor for Managing Parkinson's Disease by Regulating Inflammation and Mitigating Oxidative Damage

“…[14][15][16] Although inflammation serves as a defense mechanism, sustained inflammation in the brain, can be detrimental as PD advances. [17,18] Therefore, ROS is the trigger, causing an inflammatory response that can lead to sustained secondary damage to brain tissues. Cascade of regulatory strategies to eliminate ROS and manage the subsequent inflammatory microenvironment dominated by microglia at the lesion site can serve as promising treatment avenues for treating PD.…”