Parkinson's disease (PD) is a progressive neurological disorder cause by the degeneration of dopaminergic neurons, resulting in uncontrollable movements such as stiffness, tremors, and difficult with coordination. This neurodegenerative disease can also manifest as a speech disorder, hallucinations, and dementia, a variety of symptoms that scientists have found difficult to develop therapies for. And even if the current treatments can alleviate symptoms, this disease as well as other neurodegenerative disorders, known as synucleinopathies, will progress until they are untreatable, always resulting in death. This sad reality is grounds for many neuroscientists and researchers to dive deeper in to the causes of neurodegeneration and how to stop progression before it becomes unbeatable.
A major and important finding in the study of Parkinson's and other neurodegenerative diseases is the role of alpha-synuclein, which is a neuronal presynaptic protein that regulates vesicular trafficking and neurotransmitter release. When this protein aggregates or becomes misfolded, which it is very susceptible to do, it leads to neurotoxicity and subsequent neuronal death. Dr. Momoko Takahashi, who presented her and her colleagues' research to our class, and Dr Paolo Calabresi et al. have used this knowledge on alpha-synuclein in their research, which have the same goals but different approaches to studying the protein.
Dr. Calabresi's research article begins with the discussion of alpha-synuclein and its role in contributing the PD, focusing on its aggregates perturbing "dopaminergic transmission and inducing presynaptic and postsynaptic dysfunctions" (Calabresi). Alpha-synuclein causes many different forms of synaptic dysfunction, including disruption of release and uptake of neurotransmitters, damage to synaptic enzyms, and impairment of synaptic plasticity. These researchers have found recent evidence that alpha-synuclein-induced synaptic dysfunction occurs prior to neuronal death, suggesting that targeting synaptic dysfunction early may be a promising therapeutic strategy for synucleinopathies.
In the research performed by Dr. Takahashi et al., these scientists also aimed to identify molecular causes of PD based on existing knowledge of alpha-synuclein's contribution to neuronal death. Rather than focusing on synaptic dysfunction, Takahashi and her fellow researchers discuss misfolded and aggregated a-syn's effect on SNARE protein Ykt6, which plays a role in vesicular trafficking and trafficking of protein involved in long-term potentiation. These Ykt6 proteins are very abundant in the hippocampus, suggesting that if their activity is affected it can lead to dementia, a symptom of PD and other synucleinopathies. The researchers also discussed the neurotoxic effects of an unbalanced amount of calcineurin, a calcium-dependent protein, present in the brain because of calcium's necessity in long-term potentiation. These findings led the researchers to discussion of new pharmacological therapies that are calcineurin inhibitors, intending to prevent neurotoxicity and subsequent neuronal death.
Both groups of researchers have big goals to treat deteriorating neural conditions before irreversible call death occurs, with hopes that the therapies that will be developed as a result of their research will attack synucleinopathy diseases before they progress into a terminal state. There is still so much to learn and understand about neurodegenerative disorders, but with neuroscientists like Dr. Takahashi, Dr. Calabresi, and their colleagues, the reality of highly effective therapies and even cures to these diseases is becoming increasingly more imaginable.
Sources:
www.nature.com/articles/s41410-023-05672-0
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