Parkinson disease: the old hidden polyamine transport mystery finally unveiled

Aging is the major risk factor for many chronic disorders, including diabetes mellitus, cancer, cardiovascular diseases, and neurodegenerative diseases including Parkinson disease (PD), whose current treatment is limited to symptomatic relief. Because PD prevalence increases with age, the number of sick patients is estimated to double from 6.9 million in 2015 to 14.2 million in 2040. Although age‐related molecular mechanisms of PD (eg, dopamine metabolism, iron accumulation, mitochondrial DNA changes, and decreased protein‐degradation efficiency) have been proposed, no corresponding blood biomarkers have been validated for widespread clinical use. Alpha-synuclein protein is currently the most studied factor driving the disease. Blood‐based biomarkers associated with aging‐related risk for PD would enable efficient monitoring of the disease process and could be used for development of therapies. Around twenty genetic defects have already been linked to the disease, but for several of these genes, scientists still don’t know what function they fulfil. The ATP13A2 gene used to be one of these genes, but researchers at KU Leuven have now discovered its function in the cell, explaining how a defect in the gene can cause Parkinson’s disease.

Researchers have discovered that a defect in the ATP13A2 gene causes cell death by disrupting the cellular transport of polyamines. When this happens in the part of the brain that controls body movement, it can lead to Parkinson’s disease. The team discovered that polyamines enter the cell via lysosomes and that ATP13A2 transfers polyamines from the lysosome to the cell interior. This transport process is essential for lysosomes to function properly as the ‘waste disposal system’ of the cell where obsolete cell material is broken down and recycled. However, mutations in the ATP13A2 gene disrupt this transport process, so that polyamines build up in lysosomes. As a result, the lysosomes swell and eventually burst, killing the cells. When this happens in the part of the brain that controls body movement, this process may trigger the motion problems and tremors related to Parkinson’s disease. Several lines of evidences have shown changes in CSF polyamine levels in patients with various diseases including brain tumors, inflammation, and neurodegeneration. In PD compared with controls, a polyamine called spermidin decreases whereas putrescine increases in CSF and decreases in red blood cells, while no significant changes in Spd and Spm in the basal ganglia have been reported.

Polyamines are essential molecules that support many cell functions and protect cells in stress conditions. But how polyamines are taken up and transported in human cells was still a mystery. The team realized that ATP13A2 transports polyamines and is crucial for their uptake into the cell. Unravelling the role of ATP13A2 is an important step forward in Parkinson’s research and sheds new light on what causes the disease, but a lot of work remains to be done. Professor Peter Vangheluwe explained: “We now have to investigate how deficient polyamine transport is linked to other defects in Parkinson’s disease such as the accumulation of plaques in the brain and malfunctioning of the mitochondria. We need to examine how these mechanisms influence each other. The discovery of the polyamine transport system in animals has implications beyond Parkinson’s disease as well, because polyamine transporters also play a role in other age-related conditions, including cancer, cardiovascular diseases, and several neurological disorders. Now that we have unravelled the role of ATP13A2, we can start searching for molecules that influence its function. Our lab is already collaborating with the Centre for Drug Design and Discovery and receives support from the Michael J. Fox Foundation”.

  • Edited by Dr. Gianfrancesco Cormaci, PhD, specialist in Clinical Biochemistry.

Scientific references

Saiki S et al., Hattori N. Ann Neurol. 2019; 86(2):251-63.

Perni M et al. ACS Chem Biol. 2018 Aug; 13(8):2308-19. 

Sharma S et al. Neurochem Int. 2018 Jun; 116:104-111.

Informazioni su Dott. Gianfrancesco Cormaci 2444 Articoli
- Laurea in Medicina e Chirurgia nel 1998 (MD Degree in 1998) - Specialista in Biochimica Clinica nel 2002 (Clinical Biochemistry specialty in 2002) - Dottorato in Neurobiologia nel 2006 (Neurobiology PhD in 2006) - Ha soggiornato negli Stati Uniti, Baltimora (MD) come ricercatore alle dipendenze del National Institute on Drug Abuse (NIDA/NIH) e poi alla Johns Hopkins University, dal 2004 al 2008. - Dal 2009 si occupa di Medicina personalizzata. - Detentore di un brevetto sulla preparazione di prodotti gluten-free a partire da regolare farina di frumento immunologicamente neutralizzata (owner of a patent concerning the production of bakery gluten-free products, starting from regular wheat flour). - Responsabile del reparto Ricerca e Sviluppo per la società CoFood s.r.l. (leader of the R&D for the partnership CoFood s.r.l.) - Autore di un libro riguardante la salute e l'alimentazione, con approfondimenti su come questa condizioni tutti i sistemi corporei. - Autore di articoli su informazione medica, salute e benessere sui siti web e