Alzheimer's disease and Parkinson's disease are the two most common neurodegenerative diseases. However, the pathological features of the two, the affected brain parts and clinical symptoms are very different. In the brains of patients with Alzheimer's disease, tangles formed by beta amyloid plaques and tau proteins cause neuronal cell death in the hippocampus and prefrontal cortex, degrading cognitive and memory functions in patients. . In patients with Parkinson's disease, the Lewis body formed by the α-synuclein protein mainly affects the substantia nigra of the midbrain, resulting in impaired motor function.
Behind these different surface phenomena, both diseases are caused by the abnormal folding of proteins, which affects nerve cell function and even death. So is there any common mechanism between them? A recent study by Singaporean scientists has found a common link between the two, the part of the beta-amyloid precursor app protein called AICD, which has strong neurotoxicity and plays a role in both disease processes. The important role. The study was published in the recent issue of Science, Science Signaling.
Scientists from the National University of Singapore (NUS) started the study from Parkinson's disease. As with Alzheimer's disease, a small percentage of patients with Parkinson's disease are hereditary. Among the genetic mutations that cause Parkinson's disease, the LRRK2 gene is more common. The LRRK2 gene encodes a kinase. Previous studies have found that mutations that cause Parkinson's disease increase the activity of this kinase, but how to cause neurotoxicity after increased LRRK2 kinase activity is unclear.
Researchers first looked for possible substrates for LRRK2 kinase in a human cell line in an attempt to find a link between neurotoxicity. Unexpectedly, one of the substrates they found was an APP protein that plays an important role in Alzheimer's disease. APP is a transmembrane protein, and its extracellular portion can be cleaved by the action of endonucleases. This part is beta amyloid. However, its intracellular part, called AICD, does not introduce much attention. LRRK2 is capable of phosphorylating a specific site Thr-668 in the intracellular portion of the app protein, and this site can only be phosphorylated by LRRK2.
Further studies have also found that after phosphorylation of Thr-668, it can increase the level of AICD. Subsequently, the phosphorylated AICD can be transferred into the nucleus and function as a transcription factor. It has been found in neuronal cells cultured in vitro that phosphorylated AICD is toxic to cells after entering the nucleus, a process that accelerates the death of nerve cells. If the app protein in a nerve cell is genetically engineered to prevent phosphorylation of the Thr-668 site, the cell is resistant to the toxicity of the LRRK2 mutation.
The researchers then performed experiments in a mouse model carrying the LRRK2 mutation, which confirmed the above findings in the cell. In such transgenic mice, increased kinase activity due to LRRK2 mutations resulted in increased phosphorylation of the Thr-668 site on the APP protein, as well as an increase in AICD levels. More phosphorylated AICD was observed in the nucleus of transgenic mice compared to control mice, and selectively caused death of dopaminergic neurons in the substantia nigra of the midbrain. The researchers then used a LRRK2 kinase inhibitor in this mouse. After the activity of LRRK2 was inhibited, the phosphorylation level of app was significantly reduced, and the resulting neurotoxicity was also significantly reduced.
Finally, the researchers obtained brain tissue donated by some patients with Parkinson's disease with LRRK2 mutations. The analysis found that the phosphorylation level of the Thr-668 site on the APP protein in the brain of the patient increased significantly. This confirms the important role of app in the pathogenesis of patients with hereditary Parkinson's disease.
The Singapore research team believes that although Alzheimer's disease research focuses on the production of beta amyloid by APP protein, some studies have found that the intracellular part of app's AICD is also neurotoxic in Alzheimer's disease. It can also cause nerve cell death and has a certain role in the development of the disease. Therefore, if you can find a drug that effectively inhibits the production of AICD or its function, then it is expected to treat both the extensive neurodegenerative diseases of Alzheimer's disease and Parkinson's disease.
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