Overview of Parkinson’s Disease (PD)
- Parkinson’s Disease (PD) is a progressive neurodegenerative disorder that affects movement and non-motor functions.
- It is the second most common neurodegenerative disease, after Alzheimer’s, with increasing prevalence as the global population ages.
Motor Symptoms
- PD motor symptoms typically emerge after a significant (70%) loss of striatal dopamine levels. These symptoms include:
- Bradykinesia: Slowness of movement.
- Rigidity: Muscle stiffness and resistance to movement.
- Resting Tremor: Involuntary shaking, especially noticeable when muscles are relaxed.
- Ataxia: Loss of coordination and balance.
- Postural Instability: Difficulty maintaining upright posture, often leading to falls.
Non-Motor Symptoms
- Non-motor symptoms often appear before motor symptoms and severely affect the quality of life. They may include:
- Sleep disturbances.
- Constipation.
- Depression.
- Cognitive impairment.
- Loss of smell (anosmia).
Neuropathology
- Loss of Dopaminergic Neurons: The primary hallmark of PD is the degeneration of dopamine-producing neurons in the substantia nigra pars compacta (SNpc), leading to the depletion of dopamine in the striatum.
- Lewy Bodies and Lewy Neurites: These abnormal protein aggregates are central to PD pathology:
- Lewy Bodies are made up of misfolded α-synuclein protein and accumulate in the cell body.
- Lewy Neurites are abnormal aggregates found in the axons and dendrites.
Pathogenesis of Parkinson’s Disease
PD pathogenesis involves multiple overlapping mechanisms:
1. α-Synuclein Aggregation and Spreading
- α-Synuclein, a protein abundant in neurons, misfolds and aggregates, forming toxic deposits that contribute to neuronal death.
- Genetic mutations in the SNCA gene, which encodes α-synuclein, can cause familial PD.
- Misfolded α-synuclein is thought to spread between cells, exacerbating the disease.
- Braak’s Hypothesis suggests that α-synuclein pathology may start in the peripheral nervous system (e.g., the gut) and spread to the brain via the vagus nerve.
2. Mitochondrial Dysfunction
- Mitochondria are crucial for cellular energy production, and dysfunction in these organelles is implicated in PD.
- Mutations in genes associated with mitochondrial function (e.g., PARK2, PARK6) can lead to familial PD.
- Oxidative Stress: An imbalance between reactive oxygen species (ROS) and antioxidants damages mitochondria, contributing to neuronal death.
3. Lysosomal and Autophagy Dysfunction
- Lysosomes degrade and recycle cellular waste, while autophagy is the process by which cells break down damaged components.
- Dysfunction in these pathways leads to the accumulation of misfolded proteins, such as α-synuclein.
- Mutations in genes affecting lysosomal function (e.g., GBA1) significantly increase the risk of PD.
- 4. Neuroinflammation
- Glial Cells (microglia and astrocytes) become activated in PD, causing neuroinflammation, which further damages neurons.
- Peripheral immune cells, such as T lymphocytes, can infiltrate the brain, contributing to chronic inflammation.
- Inflammation is believed to play an early role in PD progression, exacerbating neurodegeneration.
Conclusion
Parkinson’s disease is a complex disorder with multiple contributing factors, including genetic mutations, mitochondrial dysfunction, impaired protein degradation, and neuroinflammation.
Understanding these mechanisms is essential for developing therapies that target these pathways and slow disease progression.
References
- The Lancet. (2023). Advances in neurodegenerative disease research: Clinical and therapeutic perspectives. The Lancet, 402(10406), 1482-1491.
- Kaufer, D., & Payne, M. (2021). Neurodegenerative Diseases. In StatPearls. StatPearls Publishing.
- Meunier, C. N. J., & Dubois, B. (2023). New insights into Alzheimer’s disease: From molecular mechanisms to clinical applications. Nature Reviews Neuroscience, 24, 16-29.
- Wu, Y., & Leung, H. H. (2021). Advances in neuroimaging techniques for neurodegenerative diseases. Frontiers in Neurology, 12, 666737.
