Abnormal accumulation of proteins in neurodegenerative disorders

By | June 29, 2021
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Increasing age is known to be the greatest risk factor for abnormal protein accumulation in the brain leading to disorders like dementia and Alzheimer’s disease

Alzheimer’s disease: A microtubule-binding protein called tau abnormally aggregates in the nerve cells, glia, and extracellular space in Alzheimer’s disease. These accumulated tau molecules are highly phosphorylated and are arranged into long, thin polymers that wind around one another to form helical filaments. The helical filaments form bundles in dendrites, axon, and cell bodies that leads to the formation of neurofibrillary tangles. The tangles are not bound to the microtubule and are highly insoluble. Hence. the tangles disturb the polymerization of the microtubule and interfere in axonal transport. This is further complicated since the tau is not proteolytically degraded. This gives an abnormal shape to the neuron.

Such tau accumulations are also found in other neurological disorders such as dementia, movement disorders and disorders related to frontal and temporal lobes.

In addition, peptide beta-amyloid also accumulates in the extracellular space of the neurons. The amyloid precursor is an integral membrane protein that is processed by proteolytic enzymes into a small proteolytic product, beta-amyloid. This process requires the enzyme beta-secretase. For unknown reasons, an abnormal amount of precursor amyloid is processed by beta-secretase in Alzheimer’s disease. Some patients show mutations in precursor amyloid gene or membrane protein genes, presinilin 1 or 2, that are closely associated with the beta-secretase activity.

Parkinson’s disease: Alpha-synuclein abnormally aggregates in the cell bodies of neurons. Alpha-synuclein is also a soluble component of the cell, like tau, in Alzheimer’s disease. These insoluble spherical inclusions are called Lewy bodies. The Lewy bodies also contain ubiquitin. Ubiquitin is required for degradation of the proteins. Apparently in Parkinson’s disease, this does not occur which might be due to abnormal accumulation of proteins or defective proteolytic processing of the cell.

Such abnormal protein accumulation might be due to altered post-translational modifications of proteins. This aggregation disrupts the axonal and dendritic membrane trafficking. Blocking such trafficking leads to deleterious effects such as synaptic activity, normal cellular activity and degeneration of the neuron because of its toxicity.

Epigenetics plays a major role in such abnormal accumulation proteins, learn the basics of epigenetics and its influence on human behavior here.