Chapter 107
Neurodegeneration — 13
As Alzheimer’s is substantially driven by β-amyloid accumulation, so Parkinson’s is driven by α-synuclein protein accumulation. There are many routes to a surfeit of α-synuclein, including mutations in genes, the most common one being in SNCA, which encodes for the synuclein protein. Mitochondrial dysfunction, impaired waste disposal, immune activation, and cell-to-cell spread of the toxic protein also contribute to the problem. Whatever the route, the result is microglial activation, activation of the innate and adaptive immune response, substantial neuroinflammation, dysfunction of synapses, and loss of neurons.
Single-cell sequencing investigating the loss of neurons related to the neurotransmitter dopamine in a part of the midbrain (the substantia nigra) identified a family of affected cells that appear critical to the progression of the disease. Single-nuclei sequencing raised the potential that not just microglia but also a subtype of oligodendrocytes have a role. Such zooming in on cells and nuclei generates new insights for how Parkinson’s takes hold in the brain.
But Parkinson’s disease is not only a brain disorder. It is one of chronic inflammation that especially affects the gastrointestinal tract, with symptoms of difficulty in swallowing, constipation, delayed gastric emptying, and irritable bowel syndrome, which are concurrent or may even precede the diagnosis of Parkinson’s. The gut symptoms can precede the Parkinson’s motor symptoms by decades. Substantial crosstalk occurs between the gut and brain, with potential spread of α-synuclein from the gut via the vagus nerve to the brain. A recent finding that patients with inflammatory bowel disease produce α-synuclein lent further credence to Braak’s hypothesis that the disease can or does originate in the gastrointestinal tract’s enteric nervous system.
There is a substantial genetic component to Parkinson’s with mutations in autosomal dominant genes (LRRK2 is the most common, also SNCA and VPS35) and autosomal recessive (PRKN, PIKN1, DJ1). Polygenic risk based on nearly 90 genome variants accounted for up to 36 percent of the heritability of the disease. Separately, a polygenic risk score for cognitive impairment that can occur in Parkinson’s has been developed. A treatment someday to preserve mitochondrial function may come from the recent discovery of a protective mitochondrial gene variant (promising about 50% less risk of developing Parkinson’s). As might be anticipated, individuals with an APOE4 allele, who also develop Parkinson’s, have an increased risk of dementia.
Figure 7.6. Risk and protective factors for development of Parkinson’s disease. Adapted from Yoav Ben-Shlomo et al., “The epidemiology of Parkinson’s disease,” Lancet 403, no. 10423 (January 2024): 283–92, https://doi.org/10.1016/S0140-6736(23)01419-8.
The risk of developing Parkinson’s (fig. 7.6) increases as we age, and with exposure to neurotoxins such as pesticides, air pollution, or microplastics, and lower socioeconomic status. Physical activity, caffeine, and—would you believe?—cigarette smoking appear to reduce the risk. I don’t recommend taking up the latter. Diets with high vegetables, fruits, and grains are linked with lower risk, while high fat and diets high in ultra-processed foods are associated with increased risk.