Parkinson's disease is a chronic neurodegenerative disorder marked by shaking, rigidity and slowness of movement. The disease affects around ten million people worldwide, usually beginning as they enter their fifties and sixties. The cause of Parkinson’s disease is not fully characterised, but is believed to involve both genetic and environmental factors and has been linked to decreased dopamine production in the substantia nigra region of the midbrain. World Parkinson’s Day on 11 April 2017 marked 200 years since Parkinson’s disease was first recognised as a medical condition. In support, Disease Models & Mechanisms (DMM) has put together a short collection of the most recent and popular Parkinson’s disease research published in DMM. All articles are fully Open Access and free to read.
The urgent case for better therapeutics
This year, during Parkinson’s Awareness Week (10-16 April 2017), support and research organisations are pushing for the development of better treatments, as the last significant drug discovery for Parkinson’s was over 50 years ago. In addition, there is no currently available cure for the disease or treatment to prevent it from progressing; only drugs that mask the symptoms for a time. Gabor Maasz, Zsolt Pirger and colleagues from the Balaton Limnological Institute and the University of Pecs, Hungary, investigated rat and snail parkinsonian models, and found that these models are particularly useful in studying the molecular mechanisms of the effect of PACAP, a neuroprotective agent with potential as a therapeutic for Parkinson’s disease. They also highlight the usefulness of snails as a cheap invertebrate in vivo parkinsonian model.
Currently available therapeutics against the symptoms of Parkinson’s such as neuroprotective dopamine agonists have been reported to cause side effects ranging from gastrointestinal distress, headache and dizziness to heart disease. These side effects could potentially be minimised by targeting drugs directly to affected cells through the use of nanoparticles. A research team from Aligarh Muslim University in India, led by Alim Hussain Naqvi, used a fruit fly model to test dopamine agonist bromocriptine in nanocomposite form and saw improved motor responses and decreased oxidative stress as compared with no treatment or bromocriptine alone.
The role of mitochondrial function
Impaired mitochondrial respiration has previously been reported to cause the elevated reactive oxygen species (ROS) frequently seen in the lymphoblasts of individuals with Parkinson’s disease. However, Paul Fisher from La Trobe University, Australia and his team of collaborators propose instead that the production of ROS results from the elevated expression of respiratory complex proteins. They suggest that the onset of Parkinson’s causes these cells to switch to a metabolically hyperactive state that might lead to long-term damage, and ultimately to neurodegeneration and the loss of mitochondrial function.
A new model for hereditary parkinsonism
A lack of available cellular models has hampered research into the mechanisms underlying neurodegeneration in X-linked dystonia-parkinsonism (XDP), a hereditary disorder involving progressive neurons loss. Naoto Ito, William T. Hendriks and researchers from Massachusetts General Hospital and Harvard Medical School, generated XDP induced pluripotent stem cell lines as a model system for probing cellular defects associated with the disease. Using these cells, they discovered genotypic differences in the expression of multiple TAF1 transcripts in fibroblasts and decreased expression of N-TAF1 in XDP versus control neural stem cells, confirming previous results describing an XDP-related defect in N-TAF1 expression.
These four papers highlight how current research is paving the way for a molecular understanding of Parkinson’s disease and the development of effective treatments free from side effects. However, the need for further research is urgent, and this World Parkinson’s Day DMM wishes Parkinson's UK, European Parkinson's Disease Association, Parkinson’s Life and other societies worldwide every success as they #UniteforParkinsons in their efforts to improve awareness and increase global research funding for Parkinson’s disease.
Watch out for DMM’s special issue on neurodegeneration, covering the latest research on Parkinson’s disease and other neurodegenerative disorders. Due for publication on 3 May 2017 – http://dmm.biologists.org/.
Article collection for World Parkinson’s Day
Pituitary adenylate cyclase-activating polypeptide (PACAP) has a neuroprotective function in dopamine-based neurodegeneration in rat and snail parkinsonian models
Gabor Maasz, Zita Zrinyi, Dora Reglodi, Dora Petrovics, Adam Rivnyak, Tibor Kiss, Adel Jungling, Andrea Tamas, Zsolt Pirger
Disease Models & Mechanisms 2017 10: 127-139; doi: 10.1242/dmm.027185
Effect of bromocriptine alginate nanocomposite (BANC) on a transgenic Drosophila model of Parkinson's disease
Yasir Hasan Siddique, Wasi Khan, Ambreen Fatima, Smita Jyoti, Saba Khanam, Falaq Naz, Rahul, Fahad Ali, Braj Raj Singh, Alim Hussain Naqv
Disease Models & Mechanisms 2016 9: 63-68; doi: 10.1242/dmm.022145
Immortalized Parkinson's disease lymphocytes have enhanced mitochondrial respiratory activity
Sarah J. Annesley, Sui T. Lay, Shawn W. De Piazza, Oana Sanislav, Eleanor Hammersley, Claire Y. Allan, Lisa M. Francione, Minh Q. Bui, Zhi-Ping Chen, Kevin R. W. Ngoei, Flora Tassone, Bruce E. Kemp, Elsdon Storey, Andrew Evans, Danuta Z. Loesch, Paul R. Fisher
Disease Models & Mechanisms 2016 9: 1295-1305; doi: 10.1242/dmm.025684
Decreased N-TAF1 expression in X-linked dystonia-parkinsonism patient-specific neural stem cells
Naoto Ito, William T. Hendriks, Jyotsna Dhakal, Christine A. Vaine, Christina Liu, David Shin, Kyle Shin, Noriko Wakabayashi-Ito, Marisela Dy, Trisha Multhaupt-Buell, Nutan Sharma, Xandra O. Breakefield, D. Cristopher Bragg
Disease Models & Mechanisms 2016 9: 451-462; doi: 10.1242/dmm.022590