Effect of amyloids on the vesicular machinery: implications for somatic neurotransmission

Abstract

Certain neurodegenerative diseases are thought to be initiated by the aggregation of amyloidogenic proteins. However, the mechanism underlying toxicity remains obscure. Most of the suggested mechanisms are generic in nature and do not directly explain the neuron-type specific lesions observed in many of these diseases. Some recent reports suggest that the toxic aggregates impair the synaptic vesicular machinery. This may lead to an understanding of the neuron-type specificity observed in these diseases. A disruption of the vesicular machinery can also be deleterious for extra-synaptic, especially somatic, neurotransmission (common in serotonergic and dopaminergic systems which are specifically affected in Alzheimer's disease (AD) and Parkinson's disease (PD), respectively), though this relationship has remained unexplored. In this review, we discuss amyloid-induced damage to the neurotransmitter vesicular machinery, with an eye on the possible implications for somatic exocytosis. We argue that the larger size of the system, and the availability of multi-photon microscopy techniques for directly visualizing monoamines, make the somatic exocytosis machinery a more tractable model for understanding the effect of amyloids on all types of vesicular neurotransmission. Indeed, exploring this neglected connection may not just be important, it may be a more fruitful route for understanding AD and PD.

Dopamine transporter forms stable dimers in the live cell plasma membrane in a phosphatidylinositol 4,5-bisphosphate–independent manner

“…Oligomerization has been proposed to play a critical role in the regulation of cellular function including signal transduction and immune response (9, 10) as it may offer stability, higher order complexity, and compartmentalization of reactions (11). Oligomers could also have deleterious effects on cells as observed in the case of neurodegenerative disorders (12–14). For a large number of proteins, there are specific binding domains that facilitate or modulate oligomerization (15, 16).…”

Predicting Amyloidogenic Proteins in the Proteomes of Plants

“…The propensity of a protein to form amyloid fibrils is determined by the presence in its amino acid sequence of so-called “amyloidogenic regions” (ARs) that drive amyloidogenesis [ 29 , 30 , 31 ] acting as a “trigger” for polymerization [ 32 ]. Amyloid-forming proteins may contain one or multiple ARs [ 33 , 34 ], which are relatively short [ 35 ] and predominantly composed of hydrophobic residues, especially aromatics (W, F, Y) and aliphatics (V, I, L) [ 36 ]. ARs can be predicted using a wide range of algorithms, one of the most efficient of which is Waltz [ 37 ], which is based on a position-specific scoring matrix [ 36 , 37 ].…”

Release of chemical transmitters from cell bodies and dendrites of nerve cells

“…Small soluble oligomers of amyloidogenic proteins have been implicated in Alzheimer's and Parkinson's diseases [43]. However, the pathway leading to toxicity remains obscure.…”