Parkinson unwanted: dyskinesia culprit found to stem from a master G protein (related) nanny

Dopamine is a neurotransmitter and hormone that plays a key role in movement, learning, memory, motivation, and emotion. Parkinson’s develops when dopamine-producing neurons in a region of the mid-brain called the substantia nigra stop working or die. It’s a brain region associated with both movement initiation and reward, so its impairment causes a wide variety of symptoms, including stiffness, balance problems, walking difficulty, tremor, depression and memory issues. Doctors treat Parkinson’s with dopamine replacement therapy, often a medicine called levodopa. The brain converts Levodopa into dopamine, and at proper doses, this leads to resolution of symptoms. But as dose and duration grow, a side effect called dyskinesia can develop. After a decade, about 95% of Parkinson’s patients will experience some degree of involuntary dyskinesia. Many people with Parkinson’s disease eventually develop debilitating movements called dyskinesia, a side effect of their much-needed dopamine replacement drugs. The mechanism underlying this unwanted side effect has been unknown, until now. An international collaboration led by Scripps Research, Florida has found a key cause, and with it, potentially, a new route to providing relief.

Dopamine replacement therapy makes Parkinson’s symptoms much better at first, but eventually treatment gives way to uncontrollable, jerky body movements. But why? New research shows that underlying this development is the therapy’s unintended boost of a protein with the unwieldy name Ras-guanine nucleotide-releasing factor 1, or RasGRP1 for short. This boost in RasGRP1 produces a cascade of effects which lead to abnormal, involuntary movements known as LID, or L-DOPA-induced dyskinesia. Encouragingly, the collaboration found that in dopamine-depleted mice and other animal models, inhibiting production of RasGRP1 in the brain during dopamine replacement diminished the involuntary movements without negating the useful effects of the dopamine therapy. G protein Ras is a pivotal cellular mediator of thousand of stimuli induced by environment, nervous activity, hormones, neurotransmitters and so forth. To work porperly, Ras needs nucleotide cofactors, namely guanosine triphosphate (GTP). Once bound with GTP is “on” and it regulates downstream proteins and signaling patways. Ras itself has enzymatic activity although relatively slow; it is needed to break GTP down to GDP, since in its GDP bound form Ras protein is “off”.

Ras protein, however, may be regulated to transform GTP into GDP by bigger proteins. Roughly, major Ras regulators are:

  • RasGAP: it enhances GTP breakdown into GDP, and deactivates Ras;
  • RasGIP1: it interferes with Ras blocking its loading with GTP;
  • Sos1: is a major activator of Ras proteins, loading GTP in Ras structure; in other words it works like the RasGRP1 protein discusses here.

However, Sos1 is activated by growth factors interaction with their receptors; RasGRP1 activity, instead, is triggered by diacyl-glycerol (DAG), a lipid byproduct of membrane phospholipid breakdown. DAG and IP3 are two common intracellular second messengers produced by the activation of hundreds of membrane receptors for hormones and neurotransmitters. Among dopamine receptors (five acknowledged), the D2 type is coupled with DAG generation, while the other major type, D1R, mediates dopamine responses through the cyclic AMP signaling pathway. They may eventually lead to activate the MAP-kinase signaling, though temporally staggered. However, Ras activation by RasGRP1 does not lead exclusively to MAP-kinases ERK1 and 2, but also to stress kinases JNK1 and/or JNK2. These may well be responsible for the onset of dyskinesia.

Srinivasa Subramaniam, PhD, associate professor of Neuroscience at Scripps Research, Florida, and his group have long been interested in cellular signaling in the brain underlying motor movements, and how it is affected by brain diseases, including Huntington’s and Parkinson’s. Dyskinesia is different than tremor and include symptoms like wriggling, fidgeting, writhing and body swaying. Despite this, many people say they prefer dyskinesia over stiffness or decreased mobility. Others, though, have painful dyskinesia or movements that interfere with exercise or social or daily activities. The reason for its development has eluded scientists. Subramaniam and his team had studied the problem over the past decade, leading them eventually to the discovery that RasGRP1 signaling was a main culprit. They already had hints in 2016, when they realized that some side effects of drugs of abuse like methamphetamine caused dyskinesia, and RasGRP1 protein was involved in the process. The next steps in the research will be discovering the best route to selectively reducing expression of RasGRP1 in the striatum while not affecting its expression in other areas of the body.

On the purpose, Dr Subramaniam commented and concluded: “There is an immediate need for new therapeutic targets to stop L-DOPA-induced dyskinesia in Parkinson’s disease. The treatments now available work poorly and have many additional unwanted side effects. We believe this represents an important step toward better options for people with Parkinson’s. The good news is that in mice, a total lack of RasGRP1 is not lethal, so we think that blocking RasGRP1 with drugs, or even with gene therapy, may have very little or no major side effects also in man”.

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

Scientific references

Eshraghi M et al. Science Advances 2020 May 1.

Shahani N et al. Sci Signal. 2016 Nov 15; 9(454):ra111.

Crittenden JR et al. PNAS USA 2009; 106(8):2892-96. 

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Informazioni su Dott. Gianfrancesco Cormaci 2450 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 salutesicilia.com e medicomunicare.it
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