NRSC 4132 Blog

Many types of neurodegenerative diseases are the result of the malfunction of a particular brain system. For example the Parkinson?s disease is the result of a failure in the substantia nigra. This is believed to be caused by a down regulation of dopamine (and in fact Parkinson-like symptoms can be a side-effect to some anti-depressants that down regulate dopamine.)
In Neuron (July 14th 2011) an article entitled ?Selective Neuronal Vulnerability in Neurodegenerative Diseases: from Stressor Thresholds to Degeneration? reviews the progress of Huntington?s Disease, Parkinson?s Disease, Alzheimer?s Disease, and amyotropic lateral sclerosis and how even though they affect particular neural subpopulations within the brain giving rise to their unique symptoms. These individual diseases often have similar manifestations despite having different apparent ?causes.?

According to the article these diseases all share certain commonalities; They are often diagnosed by the accumulation of particular proteins (where and what unique to each disease.)These diseases are all considered proteopathies which means that proteins involved in the progression or development of the disease are abnormal. These diseases also often affect similar biological pathways. Finally all of these neurodegenerative disorders? likelihood of occurrence and symptoms increase as individual ages.

These neurodegenerative disorders can be familial (where an individual inherits genetic predispositions to the disease) or can appear sporadically but, interestingly enough, the diseases show very similar symptoms and affected neural systems. Some proteins may be more likely to be misfolded in general and this misfolding may increase in the presence of cell stress. These proteins accumulate in the endoplasmic reticulum and trigger another stress response termed the unfolded protein response. Malfunctions in proteins associated with this response have been shown to cause neural degeneration in animal models and is also thought to be associated with neurodegenerative disorder development.

Each neurodegenerative disease associated misfolded protein seems to preferentially accumulate in particular neural subpopulations. This makes the similarity of how the disease acts despite the different environmental or genetic causes make sense. These misfolded proteins may become involved in signaling cascades and further affect the vulnerable neuron?s homeostasis. Malfunctions in associated homeostatic pathways have been correlated with neurodegenerative diseases as well and have been shown to exist in conjunction with the previously mention endoplasmic reticulum stress response in diseased individuals.

Studies of misfolded protein amyloid deposits (found in Alzheimer?s patients) showed that the presence of deposits accompanied neural deficits similar to the early stages of Alzheimer?s but additional depression of the local environment was present in the cases of the full blown disease. This suggests that the accumulation of misfolded proteins is not enough to cause the disease but that there may be additional stressor required. These additional stressors can be the gradual degeneration due to aging, genetic mutations in related pathways, or a number of environmental stressors.

Some subpopulations of neurons initially vulnerable to accumulation of these misfolded proteins coupled with their accompanying stress-inducing response and other genetic or environmental stresses may in fact cause neurodegenerative disorders that originate in these affected systems. These vulnerable neurons may account for the similarity of disease despite its sporadic or familial origination.