HPBCD for Treatment of Parkinson Disease

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The recent work of Jarazo et al. demonstrates that HP-β-CD ameliorates the dopaminergic neuronal loss phenotype, confirming the therapeutic potential of modulating the autophagy/lysosomal pathway in the context of Parkinson’s disease (PD).

The etiology of PD is only partially understood despite the fact that environmental causes, risk factors, and specific gene mutations are contributors to the disease. Biallelic mutations in the phosphatase and tensin homolog (PTEN)-induced putative kinase 1 (PINK1) gene involved in mitochondrial homeostasis, vesicle trafficking, and autophagy are sufficient to cause PD.

PD patient-derived cells presented differences in their energetic profile, imbalanced proliferation, apoptosis, mitophagy, and a reduced differentiation efficiency to tyrosine hydroxylase positive (TH+) neurons compared to controls’ cells. Correction of a patient’s point mutation ameliorated the metabolic properties and neuronal firing rates as well as reversing the differentiation phenotype, and reducing the increased astrocytic levels. Treatment with 2-hydroxypropyl-β-cyclodextrin increased the autophagy and mitophagy capacity of neurons concomitant with an improved dopaminergic differentiation of patient-specific neurons in midbrain organoids and ameliorated neurotoxicity in a mouse model.

Treatment with HP-β-CD increased transcription factor EB (TFEB) nuclear translocation in neurons, modified the abundance of proteins related to dopaminergic neurons differentiation, and increased dopaminergic neuron differentiation efficiency of brain organoids.

The work was performed in the frame of European Union Joint Program–Neurodegenerative Disease Research (JPND) project (INTER/JPND/14/02; INTER/JPND/15/11092422).

Jarazo, J., Barmpa, K., Modamio, J., (…), Seibler, P., Schwamborn, J.C. (2022) Parkinson’s Disease Phenotypes in Patient Neuronal Cultures and Brain Organoids Improved by 2-Hydroxypropyl-β-Cyclodextrin Treatment. Movement Disorders 37(1), 80-94. https://doi.org/10.1002/mds.28810

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