Rapidly evolving Parkinson's treatments, the future looks promising (I)

Many people became aware of Parkinson's Disease (PD) due to a prominent moment featuring the legendary boxer Ali at the 1996 Atlanta Olympics. During the opening ceremony of that Olympic Games, Ali, who was suffering from PD, trembled as he received the torch, and the whole world could see his uncontrollable shaking left hand.

Parkinson's disease (PD) was first reported by Dr. James Parkinson in 1817. In his book "An Essay on the Shaking Palsy," he described "…involuntary tremulous motion, with lessened muscular power, in parts not in action and even supported; with a propensity to bend the trunk forward, and to pass from a walking to a running pace, the senses and intellect being uninjured." Dr. Parkinson's description of the disease aligns with the modern understanding of PD, although he did not recognize the significant psychiatric and cognitive impairments associated with PD. Sixty years later, Jean-Martin Charcot, the father of modern neurology and a French neurologist, officially named the disease "Parkinson's Disease."

PD is a complex multisystem neurodegenerative disorder and the second most common neurodegenerative disease after Alzheimer's disease. The common symptoms of PD, as described by Dr. Parkinson, include bradykinesia, rigidity, tremors, freezing, muscle spasms, and dystonia. PD also involves non-motor symptoms such as sleep disorders, psychiatric symptoms, sensory disturbances, mood disorders, and cognitive impairments. PD is often referred to as the "undying cancer" as it is not fatal but afflicts patients throughout their lives. However, secondary injuries caused by PD, such as falls or dementia-related issues, can be life-threatening and pose significant challenges in the care of PD patients.

Epidemiology:

PD is the fastest-growing neurodegenerative disease, surpassing the growth rate of Alzheimer's disease. The prevalence of PD in the population aged 60 and above reaches 1% in Western countries, exceeding 4% in those aged 80 and above. In China, the prevalence rate among individuals aged 65 and above is 1.7%, similar to Western countries. Due to the large population in China, it is predicted in the 2020 edition of the Chinese Parkinson's Disease Treatment Guidelines that the number of PD patients in China will rise from 1.99 million in 2005 to 5 million in 2030, accounting for nearly half of the global PD patient population. In 2017, there were approximately 1 million PD patients in the United States, resulting in a total economic burden of $51.9 billion in medical care and nursing. It is projected that by 2037, the number of PD patients in the United States will exceed 1.6 million, with a total economic burden exceeding $79 billion. Interventions to reduce the incidence of PD, delay disease progression, and alleviate symptom burden may reduce the future economic burden of PD.

Pathogenesis:

Impaired motor coordination is a prominent symptom of PD, indicating problems in the basal ganglia of the patient's brain. The basal ganglia play a vital role in motor regulation, stability of voluntary movements, control of muscle tone, and processing of proprioceptive input impulses, all of which are involved in the formation of skilled movements. A significant portion of the basal ganglia dysfunction in PD is due to degeneration of the nigrostriatal dopaminergic pathway. Dopaminergic neurons in the substantia nigra produce dopamine, which is projected to other brain regions such as the striatum, regulating motor functions. Continuous loss of dopaminergic neurons in the substantia nigra leads to reduced dopamine secretion, and the presence of characteristic Lewy bodies in the remaining dopaminergic neurons in the substantia nigra results in functional changes in the entire basal ganglia circuit, leading to motor and cognitive impairments in patients.

Current scientific consensus suggests that the development of PD is associated with a combination of factors such as aging, genetic susceptibility, and exposure to environmental toxins. The main pathological features of PD are the loss of dopaminergic neurons in the substantia nigra and their projections to the striatum, accompanied by the formation of misfolded α-synuclein (α-syn) inclusions known as Lewy bodies and Lewy neurites, leading to apoptosis of dopaminergic neurons. Additionally, mitochondrial dysfunction, oxidative stress, neuroinflammation, and genetic mutations play important roles in dopaminergic neuron apoptosis.

Dopamine depletion:

Dopamine synthesis occurs within dopaminergic neurons, and the degeneration of these neurons is the main cause of dopamine depletion. In the dopamine synthesis pathway, L-tyrosine is first hydroxylated by tyrosine hydroxylase (TH) to form L-DOPA, which is further converted to dopamine (DA) by L-amino acid decarboxylase (DDC). Dopamine is stored in vesicles after synthesis and then transported to the presynaptic terminal. When the dendrites of neurons receive stimuli, it triggers action potentials at the axon hillock, causing the release of dopamine from vesicles into the synaptic cleft. Dopamine then binds to dopamine receptors (D1, D2, D3, and D5 receptors) on the postsynaptic neurons, participating in the regulation of movement, emotion, motivation, and reward-related behaviors. To prevent continuous stimulation of postsynaptic neurons, after dopamine has exerted its effects, the dopamine transporter (DAT) reuptakes most of the dopamine from the synaptic cleft back into presynaptic neurons. Additionally, dopamine can be degraded by monoamine oxidase (MAO) and catechol-O-methyltransferase (COMT) in the synaptic cleft or within neurons. The majority of current PD treatments target the dopamine synthesis and metabolism pathways.

α-synuclein aggregation:

α-synuclein is a soluble protein expressed in presynaptic terminals and nuclei in the central nervous system. Its physiological function is still unclear, but it is closely related to the pathogenesis of PD and associated functional impairments. α-synuclein is encoded by the SNCA gene and is naturally unfolded under physiological conditions. Mutations in the SNCA gene are often found in PD patients, resulting in abnormal α-synuclein. Abnormal α-synuclein misfolds and aggregates within cells, forming fibrils. These fibrils deposit in neuronal cells, forming Lewy bodies and Lewy neurites. Other factors may hinder the clearance of α-synuclein in the brain, such as LAMP2A gene mutations that lead to lysosomal dysfunction, preventing timely clearance of misfolded α-synuclein. Mutations in UCH-LI cause impaired ubiquitin-mediated protein degradation, resulting in defective clearance of abnormal α-synuclein. These mechanisms contribute to the accumulation of α-synuclein in neuronal cells and synapses, leading to PD-related neurodegeneration.

Mitochondrial dysfunction and oxidative stress:

The mitochondrial respiratory chain is one of the most important energy sources in organisms, efficiently converting and dissociating glucose into usable forms to provide energy. The respiratory chain reaction is accomplished in a stepwise manner by five protein complexes (Complex I-V) embedded in the inner mitochondrial membrane of eukaryotic cells. Complex I, III, and IV serve as both electron carriers and proton pumps, transferring electrons while shuttling protons (hydrogen ions) from the mitochondrial matrix through the inner membrane to the intermembrane space, establishing an electrochemical gradient. These protons ultimately generate ATP through the action of Complex V. Inhibition of these mitochondrial complexes leads to cellular energy deficiency and apoptosis. PD-like characteristics have been observed in mice exposed to the Complex I inhibitors MPTP.

Neuroinflammation

Microglia are one of the main immune cells in brain tissue, playing important roles in immune surveillance, clearance of cellular debris, synaptic pruning, and other functions in the central environment. Studies have shown that these cells are involved in the entire pathological process of Parkinson's disease (PD). The substantia nigra, a region in the brain, has the highest density of microglia, and chronic neuronal damage in the PD process activates microglia, leading to the M1 phenotype. These activated microglia release neurotoxins and inflammatory factors that exert toxic effects on neuronal cells. Additionally, dopamine neurons are highly sensitive to oxidative stress, and activated microglia are a major source of reactive oxygen species. These research findings highlight the significant role of microglia in the occurrence and development of PD.