For the best experience on the Abcam website please upgrade to a modern browser such as Google Chrome
The hallmark pathologies of Parkinson’s disease include the loss of dopaminergic neurons from the pars compacta, a portion of the substantia nigra in the midbrain, causing slowness of movement (bradykinesia), resting tremor and rigidity1. This is coupled with the presence of intracellular protein aggregates known as Lewy bodies.
Dopaminergic neurons produce the neurotransmitter dopamine, which is responsible for coordinating movement. When these neurons are lost, there is a reduction of dopamine, causing the characteristic motor symptoms of Parkinson’s disease. Motor symptoms normally emerge when the majority of dopaminergic neurons have been lost.
Lewy bodies form when misfolded alpha-synuclein (α-synuclein) aggregates into oligomers and forms β-sheet-rich fibrils. Misfolded α-synuclein can move between neurons in a prion-like fashion2, where it can act as a template to promote misfolding of normal α-synuclein. The accumulation of α-synuclein and other proteins is believed to occur long before neuronal loss3.
Despite Lewy bodies occurring in regions of neuronal loss, historically it has been difficult to establish whether their presence correlates with cell death. Debate still surrounds whether Lewy bodies are protective or neurotoxic. However, recent evidence from multiphoton imaging in mice shows selective death of Lewy body-containing neurons4, indicating that their presence is tightly correlated with cellular toxicity and therefore likely to be a pathologically relevant event in the development of Parkinson’s disease.
Most of the time, Parkinson's disease occurs sporadically, with less than 10% of cases having a familial component5. Causes of Parkinson's disease are outlined below and include oxidative stress and abnormal protein aggregation and degradation.
Mutations in six genes (SNCA, LRRK2, PRKN, DJ1, PINK1, and ATP 13A2) are known to cause Parkinson’s disease6,7. Polymorphisms in three genes (MAPT, LRRK2, and SNCA) and loss-of-function mutations in GBA are risk factors 6.
Protein aggregation and misfolding
Aggregation and misfolding of α-synuclein are believed to be critical steps in the development of Parkinson’s disease8. Protein caretaking systems such as the ubiquitin-proteasome system (UPS) and autophagy-lysosome pathway (ALP) are impaired by misfolded α-synuclein. This creates a feedback loop in which α-synuclein accumulates, further suppressing UPS or ALP function, leading to neuronal death9,10,11.
Recently, the transcription factor Lmx1b was shown to be essential for normal ALP function and for the integrity and long-term survival of dopaminergic neurons12,13.
Loss of dopamine in Parkinson’s disease causes oxidative stress. Dopamine is normally metabolized by monoamine oxidase-B, leading to the generation of hydrogen peroxide. Glutathione (GSH) normally clears excess hydrogen peroxide in the cell. Failure to do so leads to the production of reactive oxygen species (ROS) capable of initiating a cytotoxic cascade of lipid peroxidation and cell death. Reduced levels of GSH levels in Parkinson’s disease brains14, coupled with a high dopamine turnover (a compensatory mechanism for reduced dopaminergic neurons), lead to high levels of peroxidation and cellular damage.
DA quinone is another product of spontaneous and enzymatic dopamine oxidation. DA quinone is capable of causing mitochondrial dysfunction or modifying proteins, such as α-synuclein, parkin, DJ-1, and UCH-L1, whose dysfunctions are linked to Parkinson’s disease pathophysiology15,16.
Excessive mitochondrial damage contributes to Parkinson’s disease pathogenesis. Damage to mitochondria, either as a result of reduced activity of complex I in the electron transport chain, lipid membrane peroxidation by ROS, or genetic-induced alterations, can lead to the release of cytochrome c, triggering apoptosis15,16. Parkin and PINK1 for example, localize to mitochondria and are associated with normal function17. PINK1 accumulates on the outer membrane of damaged mitochondria where it recruits parkin to the dysfunctional mitochondria, triggering mitophagy18. Accumulation of dysfunctional mitochondria can lead to early-onset Parkinson’s disease18.
Dopaminergic neurons intrinsically generate high levels of ROS, making them susceptible to this chain of oxidative stress events. The progressive loss of dopaminergic neurons is associated with chronic neuroinflammation through the activation of microglia by proteins like α-synuclein, parkin, LRRK2 and DJ-119,20. Overactive or chronically activated microglia can release ROS21 and cause an uncontrolled inflammatory response, producing a self-perpetuating cycle of neurodegeneration22.
LRRK in particular is thought to be a key modulator of neuroinflammation23. LRRK is highly induced in response to α-synuclein overexpression, while LRRK2 knockout rats are resistant to neuroinflammatory responses and dopaminergic neurodegeneration following α-synuclein overexpression24.
19. Lee, E.-J. et al. α-Synuclein Activates Microglia by Inducing the Expressions of Matrix Metalloproteinases and the Subsequent Activation of Protease-Activated Receptor-1. J. Immunol. 185, 615–623 (2010).
20. Wilhelmus, M. M. M., Nijland, P. G., Drukarch, B., De Vries, H. E. & Van Horssen, J. Involvement and interplay of Parkin, PINK1, and DJ1 in neurodegenerative and neuroinflammatory disorders. Free Radic. Biol. Med. 53, 983–992 (2012).
23. Puccini, J. M. et al. Leucine-rich repeat kinase 2 modulates neuroinflammation and neurotoxicity in models of human immunodeficiency virus 1-associated neurocognitive disorders. J. Neurosci. 35, 5271–83 (2015).
24. Daher, J. P. L., Volpicelli-Daley, L. A., Blackburn, J. P., Moehle, M. S. & West, A. B. Abrogation of α-synuclein-mediated dopaminergic neurodegeneration in LRRK2-deficient rats. Proc. Natl. Acad. Sci. U. S. A. 111, 9289–94 (2014).