Abstract
The motor neuron disease amyotrophic lateral sclerosis (ALS) typically begins with localized muscle weakness. Progressive, widespread paralysis often follows over a few years. Does the disease begin with local changes in a small piece of neural tissue and then spread? Or does neural decay happen independently across diverse spatial locations? The distinction matters, because local initiation may arise by local changes in a tissue microenvironment, by somatic mutation, or by various epigenetic or regulatory fluctuations in a few cells. A local trigger must be coupled with a mechanism for spread. By contrast, independent decay across spatial locations cannot begin by a local change, but must depend on some global predisposition or spatially distributed change that leads to approximately synchronous decay. This article outlines the conceptual frame by which one contrasts local triggers and spread versus parallel spatially distributed decay. Various neurodegenerative diseases differ in their mechanistic details, but all can usefully be understood as falling along a continuum of interacting local and global processes. Cancer provides an example of disease progression by local triggers and spatial spread, setting a conceptual basis for clarifying puzzles in neurodegeneration. Heart disease also has crucial interactions between global processes, such as circulating lipid levels, and local processes in the development of atherosclerotic plaques. The distinction between local and global processes helps to understand these various age-related diseases.
Highlights
Initial symptoms of motor neuron disease present as localized muscle weakness
Does the disease arise in a localized focus of neural tissue and spread from that focal lesion? Or does the decay arise independently in diverse spatial locations?
Onset may start by local changes in a tissue microenvironment, by somatic mutation, or by various epigenetic or regulatory fluctuations in a few cells
Summary
Initial symptoms of motor neuron disease present as localized muscle weakness. Motor loss often progresses to widespread paralysis over a few years[1]. The puzzle is whether disease begins with a local change that triggers global spread or with dispersed decay over a broad spatial range. Several studies of neurodegeneration have focused on the spread of misfolded proteins in a prion-like manner[5,6] Those studies remain vague about the variety of mechanisms that influence local triggers and about the broader conceptual framing of interactions between local and global processes. The particular timing of the local and global factors differs between heart disease, cancer and neurodegeneration These age-related diseases share a common frame of interacting local and global processes that cause disease onset[14,15]. The notion of cause is always slippery and requires careful thought to frame properly
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