Parkinson’s Disease Mechanisms and Therapeutic Advances

Mechanisms and Therapeutic Advances Written by Kate Robinson Designed by Luiza Augusto Parkinson’s disease In the US, almost 90,000 people over the age of 65 are (PD) is a progressive diagnosed with PD every year. neurodegenerative While no cure exists, research is advancing to develop disease disorder primarily modifying therapies. caused by the loss of This infographic will explore the disease mechanisms underlying dopamine-producing PD and recent progress in therapeutic approaches for the disease. neurons in the brain. Symptoms of PD Over 40 symptoms exist for PD, but not everyone will experience all symptoms. Motor symptoms Cognitive changes Non-motor symptoms Bradykinesia (slow Tremors movement) Hyposomia Depression and anxiety (loss of sense of smell) Muscle stiffness Poor balance Urinary frequency Gastrointestinal issues Posture problems Sleep disorders Symptoms gradually worsen over time, making early diagnosis crucial for treatment planning. Risk factors for PD Genes involved in PD Environmental toxins As PRKN Heavy metals VPS35 Cocaine PARK7 Pesticides PINK1 Methamphetamine LRRK2 SNCA Disease mechanisms underlying PD Native a-synuclein Dendrite Dopamine Oligomers Fibrils Axon Substantia nigra Lewy body Striatum Substantia nigra Midbrain slice Transmission In PD, dopamine-producing Alpha-synuclein (a-synuclein) The aggregation of a-synuclein neurons are impaired in the is involved in intracellular leads to mitochondrial substantia nigra pars compacta, trafficking, synaptic vesicle disfunction, which in turn part of the basal ganglia – an maintenance and mitochondrial reduces energy production area of the brain that controls function. Mutations in the SNCA and increases oxidative stress, movement. Inadequate levels gene – common in PD – can lead causing further neuronal death. of dopamine lead to the motor to the misfolding of a-synuclein Chronic inflammation in the symptoms seen in PD. proteins, which aggregate, brain, caused by dysregulation forming oligomers and fibrils, of the immune system, also and creating Lewy bodies inside contributes to neuronal neurons. degeneration. Defective protein clearance in PD increases a-synuclein accumulation. Current therapeutic approaches The brain’s ability to produce and store dopamine decreases as PD progresses. Current treatments for PD mostly focus on symptomatic relief by working to restore dopamine levels. Dopamine replacement therapy NH Levodopa (L-DOPA) is the most common drug HO treatment for PD. L-DOPA is a precursor to dopamine and is usually administered alongside carbidopa to Dopamine prevent it from breaking down before it reaches the brain. Long-term L-DOPA therapy can cause motor complications, including pain, wearing-off (the HO O shortening of beneficial effects of the drug), posture HO abnormality, sleep attacks, orthostatic hypotension and psychosis. L-DOPA-induced dyskinesia can also OH develop, characterized by abnormal involuntary L-DOPA movements. NH HO Ropinirole Dopamine agonists (DAs), such as pramipexole and N ropinirole, directly stimulate dopamine receptors. S Compared with L-DOPA, DAs are associated with NH lower incidences of motor complications in early PD. DA monotherapy is suggested to delay the initiation N O of L-DOPA therapy. Pramipexole Monoamine oxidase-B (MAO-B) is an enzyme that breaks down dopamine. MAO-B inhibitors such as N HN selegiline and rasagiline can be used as monotherapy to delay L-DOPA therapy and are also used alongside L-DOPA to maintain dopamine levels. Selegiline Rasagiline Deep brain stimulation (DBS) Subthalamic nucleus In DBS, electrodes are typically surgically implanted in the and globus pallidus subthalamic nucleus or the globus pallidus interna of the brain. A neurostimulator is used to deliver continuous electrical pulses Lead through the electrodes to interrupt irregular signals that cause tremors and other movement symptoms of PD. DBS is typically used in patients who experience dyskinesias, Extension when medications wear off and aren’t effective or when side effects prevent increasing medication dose. While DBS comes with the inherent risks of a surgical procedure, this therapy has been shown to provide greater improvements in quality of life and mobility than medical treatments alone. There is also a risk of cognitive decline with DBS. Neurotransmitter Emerging and future therapies Gene Therapy Stem cell therapy In an animal study, an RNAi therapeutic targeting Intraspinal transplantation of mesenchymal stem CaV1.3 calcium channels was shown to protect cells improved neurologic function recovery and against L-DOPA-induced dyskinesias and regulated the neuroinflammatory response in a enhanced motor response to L-DOPA. Phase I first-in-human clinical trial. A glial cell line-derived neurotrophic factor In a clinical trial to determine safety, dopamine investigational gene therapy called AB-1005 was producing cells (stem cell-derived dopamine found to be well tolerated and provided stability or progenitors) will be transplanted into the brains of improvement on several motor scales in a Phase Ib people with PD. Results from this trial are expected study after 18 months. in 2027. An investigational adeno-associated virus serotype Bemdaneprocel is an investigational cell therapy 9 vector-based gene therapy, PR001, is being designed to replace dopamine-producing neurons. evaluated in patients with PD with mutation(s) in The therapy demonstrated tolerability and no the GBA1 gene. Mouse model studies indicate that serious adverse events in a Phase I study. the therapy could slow or stop disease progression. Neuroprotective drugs Targeting alpha-synuclein aggregation Lixisenatide, a glucagon-like peptide-1 receptor A Phase I study of an active immunotherapeutic agonist, has been found to have neuroprotective called UB-312 found that drug-induced antibodies properties in mouse models. The study results significantly decreased levels of aggregated suggest the drug, a type 2 diabetes treatment, a-synuclein, suggesting that UB-312 could help could slow PD progression. eliminate the buildup of harmful, toxic forms of a-synuclein. Cerebral dopamine neurotrophic factor (CDNF) reduces neuroinflammation and has Prasinezumab is a monoclonal antibody (mAb) neuroprotective effects but must be administered designed to bind a-synuclein. In individuals with intracranially. HER-096, a synthetic CDNF-like rapidly progressing PD, the mAb was found to slow molecule that can penetrate the blood–brain motor progression over a 1-year period. barrier, has displayed neuroprotective effects associated with reduced a-synuclein aggregation and neuroinflammation in an animal model. While Parkinson’s remains incurable, scientific innovation is bringing us closer to breakthrough treatments. Sponsored by HN NH