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Neurodegeneration in familal amyloidotic polyneuropathy
Author(s) -
Gasperini Robert J,
Small David H
Publication year - 2012
Publication title -
clinical and experimental pharmacology and physiology
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 0.752
H-Index - 103
eISSN - 1440-1681
pISSN - 0305-1870
DOI - 10.1111/j.1440-1681.2011.05607.x
Subject(s) - neurodegeneration , transthyretin , amyloidosis , transient receptor potential channel , calcium , polyneuropathy , toxicity , voltage dependent calcium channel , amyloid (mycology) , calcium channel , neuroscience , pathogenesis , biology , medicine , pathology , disease , receptor
Summary 1. Familial amyloid polyneuropathies (FAP) constitute a group of inherited amyloidoses that affect peripheral nerves. One common form of FAP is caused by transthyretin (TTR) misfolding and deposition in the peripheral nervous system, leading to neuronal toxicity and death. 2. The molecular mechanisms responsible for this toxicity are unclear; however, there is good biochemical and histopathological evidence that the toxicity of TTR mutations is correlated to their aggregation state. In addition, neuronal calcium dysregulation is a mechanism that has been suggested to drive the pathogenesis of FAP. 3. Amyloidogenic TTR mutations cause significant calcium influx via L‐type calcium channels in neuronal cell lines, while in primary sensory neurons, TTR mediates a calcium influx via a novel mechanism of transient receptor potential melanostatin (TRPM8) and voltage‐gated sodium and calcium channel activation. 4. Significantly, calcium dysregulation is a pathological hallmark of other neurodegenerative diseases involving amyloidosis, for example Alzheimer’s disease, and this mechanism could explain the molecular events that drive amyloid toxicity in other neurodegenerative diseases.